N-containing heteroaryl derivatives as JAK3 kinase inhibitors

ABSTRACT

N-containing heteroaryl derivatives of formula I or II, wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as JAK, particularly JAK3, kinase inhibitors.

This application is a divisional of U.S. application Ser. No. 13/504,157, filed Jun. 7, 2012 (now allowed). This application claims the benefit of U.S. application Ser. No. 13/504,157, filed Jun. 7, 2012, which is a national stage filing under 35 U.S.C. §371 of International Application No. PCT/EP2010/066476, filed on Oct. 29, 2010, which claims priority to European Patent Application No. 09382233.6, filed Oct. 29, 2009, and Provisional Application No. 61/291,051, filed Dec. 30, 2009, and Provisional Application No. 61/329,927, filed Apr. 30, 2010. The contents of all applications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a new series of N-containing heteroaryl derivative, as well as to processes for their preparation, to pharmaceutical compositions comprising them and to their use in therapy.

BACKGROUND OF THE INVENTION

The Janus kinases (JAKs) are cytoplasmic protein tyrosine kinases that play pivotal roles in pathways that modulate cellular functions in the lympho-hematopoietic system that are critical for cell proliferation and cell survival. JAKs are involved in the initiation of cytokine-triggered signaling events by activating through tyrosine phosphorylation the signal transducers and activators of transcription (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as transplant rejection and autoimmune diseases, as well as in solid and hematologic malignancies such as leukemias and lymphomas and in myeloproliferative disorders, and has thus emerged as an interesting target for drug intervention.

Four members of the JAK family have been identified so far: JAK1, JAK2, JAK3 and Tyk2. Unlike JAK1, JAK2 and Tyk2, whose expression is ubiquitous, JAK3 is mainly found in hematopoietic cells, JAK3 is associated in a non-covalent manner with the γc subunit of the receptors of IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15. These cytokines play an important role in the proliferation and differentiation of T lymphocytes. JAK3-deficient mouse T cells do not respond to IL-2. This cytokine is fundamental in the regulation of T lymphocytes. In this regard, it is known that antibodies directed against the IL-2 receptor are able to prevent transplant rejection. In patients with X severe combined immunodeficiency (X-SCID), very low levels of JAK3 expression as well as genetic defects in the γc subunit of the receptor have been identified, which indicates that immunosuppression is a consequence of an alteration in the JAK3 signaling pathway.

Animal studies have suggested that JAK3 not only plays a critical role in T and B lymphocyte maturation, but also that JAK3 is required to maintain lymphocyte function. Modulation of the immunological activity through this new mechanism can prove useful in the treatment of T cell proliferative disorders such as transplant rejection and autoimmune diseases.

JAK3 has also been shown to play an important role in mast cells, because antigen-induced degranulation and mediator release have been found to be substantially reduced in mast cells from JAK3 deficient mice. JAK3 deficiency does not affect mast cell proliferation nor IgE receptor expression levels. On the other hand, JAK3−/− and JAK3+/+ mast cells contain the same intracellular mediators. Therefore, JAK3 appears to be essential in the IgE-induced release of mediators in mast cells and its inhibition would be, thus, an effective treatment for allergic reactions.

In conclusion, JAK3 kinase inhibitors have been recognised as a new class of effective immunosuppressive agents useful for transplant rejection prevention and in the treatment of immune, autoimmune, inflammatory and proliferative diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, systemic lupus erythematosus, type I diabetes and complications from diabetes, allergic reactions and leukemia (see e.g. O'Shea J. J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Cetkovic-Cvrlje M. et al, Arch. Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82).

Accordingly, it would be desirable to provide novel compounds that are capable of inhibiting JAK/STAT signaling pathways, and in particular which are capable of inhibiting JAK3 activity, and which are good drug candidates. Compounds should exhibit good activity in in vitro and in vivo pharmacological assays, good oral absorption when administered by the oral route, as well as be metabolically stable and exhibit a favourable pharmacokinetic profile. Moreover, compounds should not be toxic and exhibit few side effects.

DESCRIPTION OF THE INVENTION

One aspect of the invention relates to a compound of formula I or II

wherein

A is carbon and B is nitrogen, or A is nitrogen and B is carbon;

W is CH or N;

R₁ and R₂ independently are hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈;

R₃ is C₁₋₄alkyl, R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hyroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl, R₁₃CONR₇—C₀₋₄alkyl, R₁₃R₇NCO—C₀₋₄alkyl, R₁₂R₇NCONR₇—C₀₋₄alkyl, R₁₃CO₂NR₇—C₀₋₄alkyl, R₁₃SO₂NR₇—C₀₋₄alkyl, —OR₁₂ or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionally substituted with one or more R₁₁;

R₅ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —OR₁₂, —NR₇R₁₂, or Cy₂-C₀₋₄alkyl, wherein Cy₂ is optionally substituted with one or more R₁₁;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl, R₁₆CO—O—C₁₋₄alkyl, cyanoC₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₁;

R₇ is hydrogen or C₁₋₄alkyl;

R₈ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, or C₁₋₄alkoxyC₁₋₄alkyl;

R₉ is halogen, —CN, —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂, —OR₁₂, —OCONR₇R₁₂, —SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or —NR₇SO₂R₁₃;

R₁₀ is C₁₋₄alkyl or R₉—C₀₋₄alkyl;

R₁₁ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —CONR₇R₁₄, —COR₁₄, —CO₂R₁₅, —OR₁₄, —OCONR₇R₁₄, —SO₂R₁₅, —SO₂NR₇R₁₄, —NR₇R₁₄, —NR₇COR₁₄, —NR₇CONR₇R₁₄, —NR₇CO₂R₁₅ or —NR₇SO₂R₁₅;

R₁₂ is hydrogen or R₁₃;

R₁₃ is C₁₋₅alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, Cy₂-C₀₋₄alkyl or R₁₄R₇N—C₁₋₄alkyl; wherein Cy₂ is optionally substituted with one or more R₁₁;

R₁₄ is hydrogen or R₁₅;

R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl;

R₁₆ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl or cyanoC₁₋₄alkyl;

Cy₁ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and

Cy₂ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂

The compounds of formula I or II are JAK, particularly JAK3, kinase inhibitors and therefore can be useful for the treatment or prevention of any disease mediated by JAKs, and particularly JAK3.

Thus, another aspect of the invention relates to a compound of formula I or II

wherein

A is carbon and B is nitrogen, or A is nitrogen and B is carbon;

W is CH or N;

R₁ and R₂ independently are hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈;

R₃ is C₁₋₄alkyl, R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl, R₁₃CONR₇—C₀₋₄alkyl, R₁₃R₇NCO—C₀₋₄alkyl, R₁₂R₇NCONR₇—C₀₋₄alkyl, R₁₃CO₂NR₇—C₀₋₄alkyl, R₁₃SO₂NR₇—C₀₋₄alkyl, —OR₁₂ or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionally substituted with one or more R₁₁;

R₅ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —OR₁₂, —NR₇R₁₂, or Cy₂-C₀₋₄alkyl, wherein Cy₂ is optionally substituted with one or more R₁₁;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₅CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl, R₁₆CO—O—C₁₋₄alkyl, cyanoC₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ or Cy₂ are optionally substituted with one or more R₁₁;

R₇ is hydrogen or C₁₋₄alkyl;

R₈ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, or C₁₋₄alkoxyC₁₋₄alkyl;

R₉ is halogen, —CN, —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂, —OR₁₂, —OCONR₇R₁₂, —SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or NR₇SO₂R₁₃;

R₁₀ is C₁₋₄alkyl or R₉—C₀₋₄alkyl;

R₁₁ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —CONR₇R₁₄, —COR₁₄, —CO₂R₁₆, —OR₁₄, —OCONR₇R₁₄, —SO₂R₁₅, —SO₂NR₇R₁₄, —NR₇R₁₄, —NR₇COR₁₄, —NR₇CONR₇R₁₄, —NR₇CO₂R₁₅ or —NR₇SO₂R₁₅;

R₁₂ is hydrogen or R₁₃,

R₁₃ is C₁₋₅alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, Cy₂-C₀₋₄alkyl or R₁₄R₇N—C₁₋₄alkyl; wherein Cy₂ is optionally substituted with one or more R₁₁;

R₁₄ is hydrogen or R₁₅;

R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl;

R₁₆ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl or cyanoC₁₋₄alkyl;

Cy₁ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and

Cy₂ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; for use in therapy.

Another aspect of the invention relates to a pharmaceutical composition which comprises a compound of formula I or II or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Another aspect of the present invention relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by JAKs, particularly JAK3. More preferably, the disease mediated by JAKs, particularly JAK3, is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is a proliferative disorder.

Another aspect of the present invention relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In a further preferred embodiment, the disease is a proliferative disorder.

Another aspect of the present invention relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, inflammatory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.

Another aspect of the present invention relates to a compound of formula I or II or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by JAKs, particularly JAK3. More preferably, the disease mediated by JAKs, particularly JAK3, is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is a proliferative disorder.

Another aspect of the present invention relates to a compound of formula I or II or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In a further preferred embodiment, the disease is a proliferative disorder.

Another aspect of the present invention relates to a compound of formula I or II or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, inflammatory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.

Another aspect of the present invention relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease mediated by JAKs, particularly JAK3. More preferably, the disease mediated by JAKs, particularly JAK3, is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is a proliferative disorder.

Another aspect of the present invention relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof for the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In a further preferred embodiment, the disease is a proliferative disorder.

Another aspect of the present invention relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, inflammatory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.

Another aspect of the present invention relates to a method of treating or preventing a disease mediated by JAKs, particularly JAK3, in a subject in need thereof, especially a human being, which comprises administering to said subject an amount of a compound of formula I or II or a pharmaceutically acceptable salt thereof effective to treat said disease. More preferably, the disease mediated by JAKs, particularly JAK3, is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is a proliferative disorder.

Another aspect of the present invention relates to a method of treating or preventing at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders in a subject in need thereof, especially a human being, which comprises administering to said subject an amount of a compound of formula I or II or a pharmaceutically acceptable salt thereof effective to treat said disease. In a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In a further preferred embodiment, the disease is a proliferative disorder.

Another aspect of the present invention relates to a method of treating or preventing a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, inflammatory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas in a subject in need thereof, especially a human being, which comprises administering to said subject an amount of a compound of formula I or II or a pharmaceutically acceptable salt thereof effective to treat said disease.

Another aspect of the present invention relates to a process for the preparation of a compound of formula I or II as defined above, which comprises:

(a) for a compound of formula I, reacting a compound of formula VI with a compound of formula III

wherein A, B, W, R₁, R₂, R₃, R₄ and R₅ have the meaning previously described in relation with a compound of formula I or II; or

(b) for a compound of formula I, reacting a compound of formula VI with a compound of formula IV

wherein A, B, W, R₁, R₂, R₃, R₄ and R₅ have the meaning previously described in relation with a compound of formula I or II; or

(c) when in a compound of formula II R₅ is hydrogen (a compound of formula IIa), reacting a compound of formula VI, as defined above, with a synthetic equivalent for the CO synthon.

wherein A, B, W, R₁, R₂, R₃ and R₅ have the meaning previously described in relation with a compound of formula I or II; or

(d) when in a compound of formula II R₆ is other than hydrogen, reacting a compound of formula IIa with a compound of formula V (R₆—X) in the presence of a base, wherein X is a leaving group; or

(e) converting, in one or a plurality of steps, a compound of formula I or II into another compound of formula I or II.

In the above definitions, the term C₁₋₅ alkyl, as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to 5 carbon atoms and includes among others the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and iso-pentyl. Likewise, the term C₁₋₄alkyl, as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to 4 carbon atoms and includes the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

A C₁₋₄alkoxy group, as a group or part of a group, means a group of formula —OC₁₋₄alkyl, wherein the C₁₋₄alkyl moiety has the same meaning as previously described. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

A C₁₋₄alkoxyC₁₋₄alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C₁₋₄alkyl group with one or more C₁₋₄alkoxy groups as defined above, which can be the same or different. Examples include, among others, the groups methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, dimethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,2-diethoxyethyl, 1-butoxyethyl, 2-sec-butoxyethyl, 3-methoxypropyl, 2-butoxypropyl, 1-methoxy-2-ethoxypropyl, 3-tert-butoxypropyl and 4-methoxybutyl.

Halogen or its abbreviation halo means fluoro, chloro, bromo or iodo.

A haloC₁₋₄alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C₁₋₄alkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different. Examples include, among others, the groups trifluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl, nonafluorobutyl, 1-chloro-2-fluoroethyl and 2-bromo-1-chloro-1-fluoropropyl.

A hydroxyC₁₋₄alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C₁₋₄alkyl group with one or more hydroxy groups. Examples include, among others, the groups hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl and 1-hydroxybutyl.

A cyanoC₁₋₄alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C₁₋₄alkyl group with one or more cyano groups. Examples include, among others, the groups cyanomethyl, dicyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 2,3-dicyanopropyl and 4-cyanobutyl.

A haloC₁₋₄alkoxy group means a group resulting from the replacement of one or more hydrogen atoms from a C₁₋₄ alkoxy group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo) which can be the same or different. Examples include, among others, the groups trifluoromethoxy, fluoromethoxy, 1-chloroethoxy, 2-chloroethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4-fluorobutoxy, nonafluorobutoxy, 1-chloro-2-fluoroethoxy and 2-bromo-1-chloro-1-fluoropropoxy.

The term C₀ alkyl indicates that the alkyl group is absent.

Thus, the term R₉—C₀₋₄alkyl includes R₉ and R₉—C₁₋₄ alkyl. The term R₉—C₁₋₄ alkyl relates to a group resulting from the substitution of one hydrogen atom of a C₁₋₄alkyl group with one R₉ group.

The terms R₁₂R₇N—C₀₋₄alkyl, R₁₃CONR₇—C₀₋₄alkyl, R₁₃R₇NCO—C₀₋₄alkyl, R₁₂R₇NCONR₇—C₀₋₄alkyl, R₁₃CO₂NR₇—C₀₋₄alkyl, R₁₃SO₂NR₇—C₀₋₄alkyl, R₁₆CO—C₀₋₄alkyl and R₁₆CO₂—C₀₋₄alkyl include —NR₇R₁₂ and R₁₂R₇N—C₁₋₄alkyl, —NR₇COR₁₃ and R₁₃CONR₇—C₁₋₄alkyl, —CONR₇R₁₃ and R₁₃R₇NCO—C₁₋₄alkyl, —NR₇CONR₇R₁₂ and R₁₂R₇NCONR₇—C₁₋₄alkyl, —NR₇CO₂R₁₃ and R₁₃CO₂NR₇—C₁₋₄alkyl, —NR₇SO₂R₁₃ and R₁₃SO₂NR₇—C₁₋₄alkyl, —COR₁₆ and R₁₆CO—C₁₋₄alkyl, and —CO₂R₁₆ and R₁₆CO₂—C₁₋₄alkyl, respectively.

A group R₁₂R₇N—C₁₋₄alkyl, R₁₄R₇N—C₁₋₄alkyl, R₁₃CONR₇—C₁₋₄alkyl, R₁₃R₇NCO—C₁₋₄alkyl, R₁₂R₇NCONR₇—C₁₋₄alkyl, R₁₃CO₂NR₇—C₁₋₄alkyl, R₁₃SO₂NR₇—C₁₋₄alkyl, R₁₆CO—C₁₋₄alkyl, R₁₆CO₂—C₁₋₄alkyl or R₁₆CO—O—C₁₋₄alkyl means a group resulting from the replacement of one hydrogen atom from a C₁₋₄alkyl group with one —NR₇R₁₂, —NR₇R₁₄, —NR₇COR₁₃, —CONR₇R₁₃, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃—NR₇SO₂R₁₃, —COR₁₆, —CO₂R₁₆ or —OCOR₁₆ group, respectively.

A Cy₁ group refers to a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic carbocyclic or heterocyclic ring, which is saturated, partially unsaturated or aromatic. When heterocyclic, it contains from 1 to 4 heteroatoms independently selected from N, S and O. Bicyclic rings are formed either by two rings fused through two adjacent C or N atoms, or through two non-adjacent C or N atoms forming a bridged ring, or else they are formed by two rings bonded through a single common C atom forming a spiro ring. Cy₁ is bonded to the rest of the molecule through any available C atom. When Cy₁ is saturated or partially unsaturated, one or more C or S atoms of said ring are optionally oxidized forming CO, SO or SO₂ groups. Cy₁ is optionally substituted as disclosed above in the definition of a compound of formula I or II, said substituents can be the same or different and can be placed on any available position of the ring system.

A Cy₂ group refers to a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic carbocyclic or heterocyclic ring, which is saturated, partially unsaturated or aromatic. When heterocyclic, it contains from 1 to 4 heteroatoms independently selected from N, S and O. Bicyclic rings are formed either by two rings fused through two adjacent C or N atoms, or through two non-adjacent C or N atoms forming a bridged ring, or else they are formed by two rings bonded through a single common C atom forming a spiro ring. Cy₂ is bonded to the rest of the molecule through any available C or N atom. When Cy₂ is saturated or partially unsaturated, one or more C or S atoms of said ring are optionally oxidized forming CO, SO or SO₂ groups. Cy₂ is optionally substituted as disclosed above in the definition of a compound of formula I or II, said substituents can be the same or different and can be placed on any available position of the ring system.

Examples of either Cy₁ or Cy₂ include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, homopiperidinyl, oxazinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, isoxazolinyl, isothiazolinyl 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 4-oxo-piperidinyl, 2-oxo-piperazinyl, 2-oxo-1,2-dihydropyridinyl, 2-oxo-1,2-dihydropyrazinyl, 2-oxo-1,2-dihydropyrimidinyl, 3-oxo-2,3-dihydropyridazyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzooxazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, cinolinyl, naphthyridinyl, indazolyl, imidazopyridinyl, pyrrolopyridinyl, thienopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyrazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, benzo[1,3]dioxolyl, phtalimidyl, 1-oxo-1,3-dihydroisobenzofuranyl, 1,3-dioxo-1,3-dihydroisobenzofuranyl, 2-oxo-2,3-dihydro-1H-indolyl, 1-oxo-2,3-dihydro-1H-isoindolyl, chromanyl, perhydroquinolinyl, 1-oxo-perhydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, 4-oxo-3,4-dihydroquinazolinyl, 2-aza-bicyclo[2.2.1]heptanyl, 5-aza-bicyclo[2.1.1]hexanyl, 2H-spiro[benzofuran-3,4′-piperidinyl], 3H-spiro[isobenzofuran-1,4′-piperidinyl], 1-oxo-2,8-diazaspiro[4.5]decanyl and 1-oxo-2,7-diazaspiro[4.5]decanyl.

When in the definitions used throughout the present specification for cyclic groups the examples given refer to a radical of a ring in general terms, for example piperidinyl, tetrahydropyranyl or indolyl, all the available bonding positions are included, unless a limitation is indicated in the corresponding definition for said cyclic group, for example that the ring is bonded through a C atom in Cy₁, in which case such limitation applies. Thus for example, in the definitions of Cy₂, which do not include any limitation regarding the bonding position, the term piperidinyl includes 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl; tetrahydropyranyl includes 2-tetrahydropyranyl, 3-tetrahydropyranyl and 4-tetrahydropyranyl; and indolyl includes 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl.

In the above definitions of Cy₁ and Cy₂, when the examples listed refer to a bicycle in general terms, all possible dispositions of the atoms are included. Thus, for example, the term pyrazolopyridinyl includes groups such as 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[1,5-a]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl and 1H-pyrazolo[4,3-b]pyridinyl, the term imidazopyrazinyl includes groups such as 1H-imidazo[4,5-b]pyrazinyl, imidazo[1,2-a]pyrazinyl and imidazo[1,5-a]pyrazinyl and the term pyrazolopyrimidinyl includes groups such as 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[4,3-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl and pyrazolo[1,5-c]pyrimidinyl.

The term Cy₂-C₀₋₄alkyl includes Cy₂ and Cy₂-C₁₋₄alkyl.

A Cy₂-C₁₋₄alkyl group means a group resulting from the replacement of one hydrogen atom from a C₁₋₄alkyl group with one Cy₂ group. Examples include, among others, the groups (piperidinyl-4-yl)methyl, 2-(piperidinyl-4-yl)ethyl, 3-(piperidinyl-4-yl)propyl, 4-(piperidinyl-4-yl)butyl, (tetrahydropyran-4-yl)methyl, 2-(tetrahydropyran-4-yl)ethyl, 3-(tetrahydropyran-4-yl)propyl, 4-(tetrahydropyran-4-yl)butyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, (indolinyl-1-yl)methyl, 2-(indolinyl-1-yl)ethyl, 3-(indolinyl-1-yl)propyl and 4-(indolinyl-1-yl)butyl.

In the definition of a compound of formula I or II, either A is carbon and B is nitrogen, or A is nitrogen and B is carbon. Thus, the compounds of formula I or II include the following types of compounds:

The expression “optionally substituted with one or more” means that a group can be substituted with one or more, preferably with 1, 2, 3 or 4 substituents, more preferably with 1, 2 or 3 substituents, and still more preferably with 1 or 2 substituents, provided that said group has enough positions susceptible of being substituted. The substituents can be the same or different and are placed on any available position.

In certain embodiments of Cy₁ mentioned below, a nitrogen atom that can be substituted means a nitrogen atom that has a hydrogen substituent.

Throughout the present specification, by the term “treatment” is meant eliminating, reducing or ameliorating the cause or the effects of a disease. For purposes of this invention treatment includes, but is not limited to, alleviation, amelioration or elimination of one or more symptoms of the disease; diminishment of the extent of the disease; stabilized (i.e. not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission of the disease (whether partial or total).

As used herein, “prevention” refers to preventing the occurrence of a disease in a subject that is predisposed to or has risk factors but does not yet display symptoms of the disease. Prevention includes also preventing the recurrence of a disease in a subject that has previously suffered said disease.

Any formula given herein is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In addition to the unlabeled form, all isotopically labeled forms of the compounds of formula I and II are included within the scope of the invention.

Any formula given herein is also intended to represent the corresponding tautomers forms. “Tautomer” refers to alternate forms of a molecule that differ in the position of a proton. Examples include, among others, enol-keto and imine-enamine tautomers, and the tautomeric forms of heteroaryl groups containing a —N═CH—NH— ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles and tetrazoles.

The invention thus relates to the compounds of formula I or II as defined above.

In another embodiment, the invention relates to a compound of formula I or II

wherein

A is carbon and B is nitrogen, or A is nitrogen and B is carbon;

W is CH or N;

R₁ and R₂ independently are hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈;

R₃ is C₁₋₄alkyl, R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl, R₁₃CONR₇—C₀₋₄alkyl, R₁₃R₇NCO—C₀₋₄alkyl, R₁₂R₇NCONR₇—C₀₋₄alkyl, R₁₃CO₂NR₇—C₀₋₄alkyl, R₁₃SO₂NR₇—C₀₋₄alkyl, —OR₁₂ or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionally substituted with one or more R₁₁;

R₅ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —OR₁₂, —NR₇R₁₂, or Cy₂-C₀₋₄alkyl, wherein Cy₂ is optionally substituted with one or more R₁₁;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₁;

R₇ is hydrogen or C₁₋₄alkyl;

R₈ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, or C₁₋₄alkoxyC₁₋₄alkyl;

R₉ is halogen, —CN, —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂, —OR₁₂, —OCONR₇R₁₂, —SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂—NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or —NR₇SO₂R₁₃;

R₁₀ is C₁₋₄alkyl or R₉—C₀₋₄alkyl;

R₁₁ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —CONR₇R₁₄, —COR₁₄, —CO₂R₁₅, —OR₁₄, —OCONR₇R₁₄, —SO₂R₁₅, —SO₂NR₇R₁₄, —NR₇R₁₄, —NR₇R₁₄, —NR₇CONR₇R₁₄, —NR₇CO₂R₁₅ or —NR₇SO₂R₁₅;

R₁₂ is hydrogen or R₁₃;

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionally substituted with one or more R₁₁;

R₁₄ is hydrogen or R₁₅;

R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl;

Cy₁ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and

Cy₂ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to a compound of formula I or II

wherein

A is carbon and B is nitrogen, or A is nitrogen and B is carbon;

W is CH or N;

R₁ and R₂ independently are hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alky, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or SR₈;

R₃ is C₁₋₄alkyl, R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₃CONR₇—C₀₋₄alkyl, R₁₃R₇NCO—C₀₋₄alkyl, R₁₂R₇NCONR₇—C₀₋₄alkyl, R₁₃CO₂NR₇—C₀₋₄alkyl, R₁₃SO₂NR₇—C₀₋₄alkyl, —OR₁₂ or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionally substituted with one or more R₁₁;

R₅ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —OR₁₂, —NR₇R₁₂, or Cy₂-C₀₋₄alkyl, wherein Cy₂ is optionally substituted with one or more R₁₁;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₁;

R₇ is hydrogen or C₁₋₄alkyl;

R₈ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, or C₁₋₄alkoxyC₁₋₄alkyl;

R₉ is halogen, —CN, —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂, —OR₁₂, —OCONR₇R₁₂, —SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or —NR₇SO₂R₁₃;

R₁₀ is C₁₋₄alkyl or R₉—C₀₋₄alkyl;

R₁₁ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —CONR₇R₁₄, —COR₁₄, —CO₂R₁₅, —OR₁₄, —OCONR₇R₁₄, —SO₂R₁₅, —SO₂NR₇R₁₄, —NR₇R₁₄, —NR₇COR₁₄, —NR₇CONR₇R₁₄, —NR₇CO₂R₁₅ or —NR₇SO₂R₁₅;

R₁₂ is hydrogen or R₁₃;

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionally substituted with one or more R₁₁;

R₁₄ is hydrogen or R₁₅;

R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl;

R₁₆ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl or cyanoC₁₋₄alkyl;

Cy₁ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and

Cy₂ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formula I.

In another embodiment, the invention relates to the compounds of formula II.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is carbon and B is nitrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon.

In another embodiment, the invention relates to the compounds of formula I or II wherein W is CH.

In another embodiment, the invention relates to the compounds of formula I or II wherein W is N.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁ and R₂ independently are hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₂ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₂ is —CN.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, more preferably hydrogen or —CN; and R₂ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁ is hydrogen or —CN.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁ is hydrogen; and R₂ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁ is —CN; and R₂ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is R₉—C₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is Cy₁, which is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is Cy₁ and Cy₁ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; wherein said Cy₁ is optionally substituted with one or more R₁₀ provided that if the ring contains a nitrogen atom that can be substituted, then said nitrogen atom is substituted with one R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is Cy₁; and Cy₁ in R₃ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is Cy₁; and Cy₁ in R₃ is a 3- to 7-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is Cy₁; and Cy₁ in R₃ is a 5- to 6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is Cy₁; and Cy₁ in R₃ is a 5- to 6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, at least one of which is N; wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is Cy₁; and Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to 6-membered saturated monocyclic ring, which is heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, at least one of which is N; wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is piperidinyl or pyrrolidinyl, preferably piperidin-3-yl or pyrrolidin-3-yl, which are optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is piperidinyl or pyrrolidinyl, preferably piperidin-3-yl or pyrrolidin-3-yl, which are substituted with one R₁₀ on the N atom of the piperidinyl or pyrrolidinyl ring and which are optionally further substituted with one or more R₁₀ groups.

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is piperidinyl or pyrrolidinyl, preferably piperidin-3-yl or pyrrolidin-3-yl, which are optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is piperidinyl or pyrrolidinyl, preferably piperidin-3-yl or pyrrolidin-3-yl, which are substituted with one R₁₀ on the N atom of the piperidinyl or pyrrolidinyl ring and which are optionally further substituted with one or more R₁₀ groups.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is piperidinyl, preferably piperidin-3-yl, which are optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is piperidinyl, preferably piperidin-3-yl, substituted with one R₁₀ on the N atom of the piperidinyl ring and optionally further substituted with one or more R₁₀ groups.

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is piperidinyl, preferably piperidin-3-yl, which are optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is piperidinyl, preferably piperidin-3-yl, substituted with one R₁₀ on the N atom of the piperidinyl ring and optionally further substituted with one or more R₁₀ groups.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is a cycle of formula

wherein Cy_(1a) and Cy_(1b) are optionally substituted with one or more further R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is a cycle of formula

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is a cycle of formula

wherein Cy_(1a) and Cy_(1b) are optionally substituted with one or more further R₁₀.

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is a cycle of formula

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is a cycle of formula Cy_(1a).

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is a cycle of formula Cy_(1a).

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is a cycle of formula

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is a cycle of formula

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is a cycle of formula Cy_(1a) and Cy_(1a) has the (S)-stereochemistry.

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is a cycle of formula Cy_(1a) and Cy_(1a) has the (S)-stereochemistry.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is a cycle of formula Cy_(1b).

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is Cy₂-C₁₋₄alkyl, wherein Cy₂ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is Cy₂-C₁₋₄alkyl; and Cy₂ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C o N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₂ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ is optionally substituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₅ is hydrogen or Cy₂; wherein Cy₂ is optionally substituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₅ is hydrogen or Cy₂; and Cy₂ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C o N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₂ is optionally substituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₆ is C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl, R₁₆CO—O—C₁₋₄alkyl, cyanoC₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₆ is C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₆ is C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl or R₁₆CO—O—C₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₆ is C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₆ is hydrogen or C₁₋₄alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₆ is C₁₋₄alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula II wherein R₆ is C₁₋₄alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula II wherein R₆ methyl.

In another embodiment, the invention relates to the compounds of formula II wherein R₆ is ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₉ is —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂, —OR₁₂, —OCONR₇R₁₂, —SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or —NR₇SO₂R₁₃, preferably R₉ is —COR₁₃.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁₀ is R₉—C₀₋₄alkyl, preferably R₉.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁₀ is R₉; and R₉ in R₁₀ is —COR₁₃ or —SO₂R₁₃. In another embodiment, the invention relates to the compounds of formula I or II wherein R₁₀ is R₉; and R₉ in R₁₀ is —COR₁₃.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionally substituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁₃ is C₁₋₅alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, more preferably methyl, isopropyl or cyanomethyl, and still more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, more preferably methyl, isopropyl or cyanomethyl, and still more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁₃ is methyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁₃ is isopropyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁₃ is cyanomethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁₃ is Cy₂-C₀₋₄alkyl wherein Cy₂ is optionally substituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₉ is —CONR₇R₁₂, —COR₁₃, —CO₂R₁₃, —OR₁₂, —OCONR₇R₁₂, —SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or —NR₇SO₂R₁₃, preferably —CO₂R₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁₀ is R₉; R₉ in R₁₀ is —COR₁₃; and R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is R₉—C₁₋₄alkyl; and

R₉ is —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂, —OR₁₂, —OCONR₇R₁₂, —SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂—NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or —NR₇SO₂R₁₃.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is R₉—C₁₋₄alkyl;

R₉ is —CONR₇R₁₂, —COR₁₃, —CO₂R₁₃, —OR₁₂, —OCONR₇R₁₂, —SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or —NR₇SO₂R₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is Cy₁, preferably piperidinyl or pyrrolidinyl, more preferably piperidinyl-3-yl or pyrrolidinyl-3-yl; wherein Cy₁ in R₃ is optionally substituted with one or more R₁₀; and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is a cycle of formula

and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃.

In another embodiment, the invention relates to the compounds or formula II wherein R₃ is a cycle of formula

and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃.

In another embodiment the invention relates to the compounds of formula I or II wherein R₃ is a cycle of formula

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉;

R₉ is —COR₁₃ or —SO₂R₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is a cycle of formula

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉;

R₉ is —COR₁₃ or —SO₂R₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is a cycle of formula Cy_(1a); and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃ still more preferably —COR₁₃.

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is a cycle of formula Cy_(1a); and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃ still more preferably —COR₁₃.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is a cycle of formula Cy_(1a);

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃, still more preferably —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is a cycle of formula Cy_(1a);

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃, still more preferably —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is a cycle of formula Cy_(1a) with (S)-stereochemistry;

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃ still more preferably —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is a cycle of formula Cy_(1a) with (S)-stereochemistry;

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃, still more preferably —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₃ is a cycle of formula Cy_(1b); and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —SO₂R₁₃.

In another embodiment, the invention relates to the compounds of formula II wherein R₃ is a cycle of formula Cy_(1b); and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —SO₂R₁₃.

In another embodiment, the invention relates to the compounds of formula I or II wherein Cy₁ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formula I or II wherein Cy₁ is a 3- to 7-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formula I or II wherein Cy₁ is a 5- to 6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formula I or II wherein Cy₁ is a 5- to 6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, at least one of which is N; wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formula I or II wherein Cy₁ is a 5- to 6-membered saturated monocyclic ring, which is heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, at least one of which is N; wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formula I or II wherein Cy₁ is piperidinyl or pyrrolidinyl, preferably piperidinyl-3-yl or pyrrolidinyl-3-yl.

In another embodiment, the invention relates to the compounds of formula I or II wherein Cy₂ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C o N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formula I or II wherein Cy₂ is a 3- to 7-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formula I or II wherein Cy₂ is a 5- to 6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formula I or II wherein Cy₂ is a 5- to 6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, at least one of which is N; wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formula I or II wherein Cy₂ is piperidinyl or pyrrolidinyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon; and

R₁ and R₂ independently are hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN; and

R₂ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon; R₁ and R₂ are hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ and R₂ independently are hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN; and

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN;

R₂ is hydrogen; and

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁ and R₂ are hydrogen; and R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN;

R₂ is hydrogen; and

R₃ is R₉—C₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN;

R₂ is hydrogen; and

R₃ is Cy₁, which is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁ and R₂ are hydrogen; and R₂ is Cy₁, which is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN;

R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN;

R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to 8-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁ in R₃ is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN;

R₂ is hydrogen; and

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon; R₁ and R₂ are hydrogen; and R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN;

R₂ is hydrogen; and

R₃ is R₉—C₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon; R₁ and R₂ are hydrogen; and R₃ is R₉—C₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN;

R₂ is hydrogen; and

R₃ is Cy₁, which is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon; R₁ and R₂ are hydrogen; and R₃ is Cy₁, which is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon:

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN;

R₂ is hydrogen; and

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, 13 OR₈ or —SR₈, and more preferably hydrogen or —CN;

R₂ is hydrogen; and

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁ in R₃ is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN;

R₂ is hydrogen; and

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry.

In another embodiment, the invention relates to the compounds of formula II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferably hydrogen or —CN;

R₂ is hydrogen; and

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen; and

R₅ is hydrogen.

In another embodiment the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon; R₁ and R₂ are hydrogen; and R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₅ is hydrogen; and

R₆ is hydrogen or C₁₋₄alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁ and R₂ are hydrogen; R₅ is hydrogen; and R₆ is hydrogen or C₁₋₄alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₅ is hydrogen; and

R₆ is C₁₋₄alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein R₁ and R₂ are hydrogen; R₅ is hydrogen; and R₆ is C₁₋₄alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ and R₂ are hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁ in R₃ is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₅ is hydrogen; and

R₆ is hydrogen or C₁₋₄alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon.

R₁ and R₂ are hydrogen;

R₅ is hydrogen; and

R₆ is hydrogen or C₁₋₄alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₅ is hydrogen; and

R₆ is C₁₋₄alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon;

R₁ and R₂ are hydrogen;

R₅ is hydrogen; and

R₆ is C₁₋₄alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀; and

R₆ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is CH;

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁ in R₃ is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is N;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is N;

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is N;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is N;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is N;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

W is N;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁ in R₃ is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon;

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁ in R₃ is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl, wherein said Cy₁ is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionally substituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl, or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionally substituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionally substituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁ which is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionally substituted with one or more R₁₁;

R₆ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionally substituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁ in R₃ is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionally substituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionally substituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon;

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionally substituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionally substituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂;

wherein Cy₂ are optionally substituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁ in R₃ is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionally substituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ is optionally substituted with one or more R₁₁; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I wherein:

A is nitrogen and B is carbon;

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ is optionally substituted with one or more R₁₁; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ is optionally substituted with one or more R₁₁; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ is optionally substituted with one or more R₁₁; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formula I wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5 to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁ in R₃ is piperidinyl or pyrrolidinyl; wherein said Cy₁ is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ is optionally substituted with one or more R₁₁; and

R₅ is hydrogen.

In another embodiment the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or NR₇R₁₂—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl, more preferably C₁₋₄alkyl and even more preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with one or more R₁₀;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or NR₇R₁₂—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl, more preferably C₁₋₄alkyl and even more preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or NR₇R₁₂—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl, more preferably C₁₋₄alkyl and even more preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN, more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ is optionally substituted with one or more R₁₀;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or NR₇R₁₂—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl, more preferably C₁₋₄alkyl and even more preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁ in R₃ is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionally substituted with one or more R₁₀;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or NR₇R₁₂—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl, more preferably C₁₋₄alkyl, and even more preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a) or Cy_(1b);

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferably C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and even more preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferably C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and even more preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

R₃ is a cycle of formula Cy_(1a) or Cy_(1b);

R₅ is hydrogen;

R₁₀ is —COR₁₃ or —SO₂R₁₃ and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

W is CH;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

W is N;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II herein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen; and

R₁₀ is —COR₁₃.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

R₃ is a cycle of formula Cy_(1a) or Cy_(1b);

R₅ is hydrogen;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferably C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and even more preferably methyl or ethyl;

R₁₀ is —COR₁₃ or —SO₂R₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferably C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and even more preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a) or Cy_(1b);

R₅ is hydrogen;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferably C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and even more preferably methyl or ethyl; and

R₁₀ is —COR₁₃ or —SO₂R₁₃.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferably C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and even more preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

W is CH;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferably C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and even more preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

W is N;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferably C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and even more preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with the (S)-stereochemistry;

R₅ is hydrogen;

R₆ is C₁₋₄alkyl, preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

W is CH;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with the (S)-stereochemistry;

R₅ is hydrogen;

R₆ is C₁₋₄alkyl, preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

W is N;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with the (S)-stereochemistry;

R₅ is hydrogen;

R₆ is C₁₋₄alkyl, preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a) with the (S)-stereochemistry;

R₅ is hydrogen;

R₆ is C₁₋₄alkyl, preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formula II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1b);

R₅ is hydrogen;

R₆ is C₁₋₄alkyl, preferably methyl or ethyl; and

R₁₀ is —SO₂R₁₃.

Furthermore, the present invention covers all possible combinations of the particular and preferred embodiments described above.

In another embodiment, the invention relates to a compound of formula I or II selected from the list of compounds described in examples 1 to 37.

In another embodiment, the invention relates to a compound of formula I or II that provides more than 50% inhibition of JAK3 activity at 10 μM, more preferably at 1 μM and still more preferably at 0.1 μM, in a JAK3 assay such as the one described in example 38.

In an additional embodiment, the invention relates to a compound according to formula I or II that provides more than 50% inhibition of JAK2 activity at 10 μM, more preferably at 1 μM and still more preferably at 0.1 μM, in a JAK2 assay such as the one described in example 39.

The compounds of the present invention contain one or more basic nitrogens and may, therefore, form salts with organic or inorganic acids. Examples of these salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid, among others. Some of the compounds of the present invention may contain one or more acidic protons and, therefore, they may also form salts with bases. Examples of these salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxylalkylamines, lysine, arginine, N-methylglucamine, procaine and the like.

There is no limitation on the type of salt that can be used, provided that these are pharmaceutical acceptable when they are used for therapeutic purposes. The term pharmaceutically acceptable salt refers to those salts which are, according to medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art.

The salts of a compound of formula I or II can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by treating a compound of formula I or II with a sufficient amount of the desired acid or base to give the salt in the conventional manner. The salts of the compounds of formula I or II can be converted into other salts of the compounds of formula I or II by ion exchange using ionic exchange resins.

The compounds of formula I or II and their salts may differ in some physical properties but they are equivalent for the purposes of the present invention. All salts of the compounds of formula I or II are included within the scope of the invention.

The compounds of the present invention may form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates. As used herein, the term solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or II or a salt thereof) and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol and the like. A complex with water is known as a hydrate. Solvates of compounds of the invention (or salts thereof), including hydrates, are included within the scope of the invention.

The compounds of formula I or II may exist in different physical forms, i.e. amorphous and crystalline forms. Moreover, the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism. Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of formula I or II, including all polymorphic forms (“polymorphs”) thereof, are included within the scope of the invention.

Some of the compounds of the present invention may exist as several diastereoisomers and/or several optical isomers. Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or on products of formula I or II. Optically pure isomers can also be individually obtained using enantiospecific synthesis. The present invention covers all individual isomers as well as mixtures thereof (for example racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physically mixing them.

The present invention further covers all unlabeled and isotopically labeled forms of the compounds of formula I or II.

The present invention further covers all tautomeric forms of the compounds of formula I or II.

The compounds of formula I or II can be obtained by following the processes described below. As it will be obvious to one skilled in the art, the exact method used to prepare a given compound may vary depending on its chemical structure. Moreover, in some of the processes described below it may be necessary or advisable to protect the reactive or labile groups with conventional protecting groups. Both the nature of these protecting groups and the procedures for their introduction and removal are well known in the art (see for example Greene T. W. and Wuts P. G. M, “Protecting Groups in Organic Synthesis”, John Wiley & Sons, 3^(rd) edition, 1999). As an example, as protecting group of an amino function the tert-butoxycarbonyl (BOC) group can be used. Whenever a protecting group is present a later deprotection step will be required, which can be performed under standard conditions in organic synthesis, such as those described in the above-mentioned reference.

In general, compounds of formula I or II can be obtained from a compound of formula VI, as shown in the following scheme:

wherein A, B, W, R₁, R₂, R₃, R₄ and R₅ have the meaning previously described in relation with a compound of formula I or II; R₆ in a compound of formula V or IIb has the meaning previously described in relation with a compound of formula I or II, except hydrogen; and X is a leaving group.

The compounds of formula I can be obtained by reacting a compound of formula VI with either the corresponding isothiocyanate III or aldehyde IV.

The reaction with an isothiocyanate III may be performed in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, in a suitable solvent such as dichloromethane, and heating at a suitable temperature usually comprised between 100 and 200° C. The heating may be thermal or by irradiating with microwaves at a wattage that allows reaching the temperature mentioned above.

The reaction between compounds of formula VI and IV can be carried out in a suitable solvent such as ethanol, butanol, N,N-dimethylformamide or dimethylacetamide, in the presence of an acid such as acetic acid, p-toluenesulfonic acid or sodium bisulfite, and heating, preferably at a temperature comprised between 100 and 200° C. The heating may be thermal or by irradiating with microwaves at a wattage that allows reaching the temperature mentioned above. When required, the reaction can be completed by subsequent addition of water.

The compounds of formula II (i.e. compounds of formula IIa and IIb) can be obtained from a compound of formula VI.

The compounds of formula IIa (i.e. a compound of formula II wherein R₆ is hydrogen) can be obtained by reaction of a compound of formula VI with a synthetic equivalent for the CO synthon. Any such synthetic equivalent disclosed in the literature can in principle be used, for example 1,1′-carbonyldiimidazole (CDI), phosgene, diphosgene or triphosgene. The reaction is conducted in the presence of a base such as N,N-diisopropylethylamine; and in a suitable solvent such as tetrahydrofuran (THF), and preferably at room temperature. The reaction can be completed by subsequent addition of water.

The compounds of formula IIb (i.e. a compound of formula II wherein R₆ is different from hydrogen) can be obtained by alkylation of a compound of formula IIa with an alkylating agent R₆—X (V), wherein X represents a leaving group and R₆ is different from H; suitable examples of X include among others halogen such as Cl, Br or I, mesylate, tosylate or triflate. This reaction may be carried out in the presence of a base such as Cs₂CO₃, K₂CO₃, NaOH, tert-BuOK or NaH, in a suitable solvent, such as acetone, toluene, 1,2-dimethoxyethane, and preferably dimethylformamide, at a suitable temperature, comprised between 0° C. and reflux.

The compounds of formula VI can be obtained by reduction of a compound of formula VII as shown in the following scheme:

wherein A, B, W, R₁, R₂, R₃ and R₅ have the meaning previously described in relation with a compound of formula I or II.

The reaction may be carried out with hydrogen gas, using a platinum catalyst, such as Pt/C in the presence of thiophene in diisopropylethylamine; in a suitable solvent such as EtOH and preferably at room temperature.

The compounds of formula VII can be obtained by reacting a compound of formula VIII with either a compound of formula IX or X, as shown in the following scheme:

wherein A, B, W, R₁, R₂, R₃ and R₅ has the meaning previously described in relation with a compound of formula I or II; and BY₂ is a boronic acid or ester.

The reaction between compounds of formula VIII and IX may be carried out using the conditions described in the literature for Suzuki's coupling reactions. For example, the reaction may be carried out in the presence of a Pd catalyst such as Pd(PPh₃)₄; in the presence of a base such as Na₂CO₃; in a mixture of solvents such as a dimethoxyethane and water; and heating.

The direct coupling between compounds of formula VIII and X can be performed using a palladium catalyst such as for example tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄) and preferably paladium(II) acetate Pd(OAc)₂ in the presence of triphenylphosphine, and a base, such as for example triethylamine and preferably potassium acetate. The reaction is usually carried out under anhydrous and anaerobic conditions. The reaction may be carried out in a solvent such as dioxane, N,N-dimethylformamide, toluene and preferably in dimethylacetamide and heating at a temperature usually comprised between 60° C.-100° C.

Compounds of formula IX and formula X can be easily obtained from commercial compounds by known methods.

Additionally, the compounds of formula VII wherein A is nitrogen and B is carbon (i.e. VIIa) can be obtained by reacting a compound of formula XI with a compound of formula XII, as shown in the following scheme:

wherein W, R₁, R₂, R₃ and R₅ have the meaning previously described in relation with a compound of formula I or II; and An is iodine, 2,4-dinitrophenolate, p-toluensulphonate or 2,4,6-trimethylbencenosulphonate.

The reaction may be carried out in the presence of tetra-n-butylammonium fluoride (TBAF) in THF and of a base such as 1,5-diazabicyclo[4.3.0]non-5ene (DBN) or 1,4-diazabicyclo[2.2.2]octane (DABCO), preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a solvent such as N,N-dimethylformamide, dimethylsulfoxide, dichloromethane, toluene or acetonitrile, preferably acetonitrile, and at a temperature comprised between −78° C. and room temperature.

Alternatively the compounds of formula VIIa can be obtained by reacting a compound of formula XII with the deprotected derivative of the compound of formula XI (XIb) obtained by using standard conditions.

The compounds of formula XII can be obtained by reaction of a compound of formula XIII with aminosulfonic acid in the presence of a H1 aqueous solution; and of a base such as K₂CO₃, NaOH or KOH; in a solvent such as dichloromethane, tetrahydrofuran, water, ethanol, methanol, isopropanol or acetonitrile; and heating preferably at reflux, as shown in the following scheme:

wherein R₁ and R₂ have the meaning previously described in relation with a compound of formula I or II; and An has the meaning described above.

The compounds of formula XI can be obtained by reaction of a compound of formula VIII with trimethylsilylacetylene, as shown in the following scheme:

wherein W, R₃ and R₅ have the meaning previously described in relation with a compound of formula I or II.

The reaction trimethylsilylacetylene may be carried out under Sonogashira conditions, using a palladium catalyst such as for example tetrakis(triphenylphosphino)palladium(0) (Pd(PPh₃)₄), preferably bis(triphenylphosphino)dichloropalladium(II) (Pd(Ph₃P)₂Cl₂) in the presence of triphenylphospine, a Cu(I) catalyst as a cocatalyst, such as CuI, and a base, such as diethylamine, N,N-diisopropylethylamine, triethylamine or isopropylethylamine. The reaction is usually carried out under anhydrous and anaerobic conditions. The reaction may be carried out in a solvent such as dioxane, N,N-dimethylformamide, tetrahydrofuran or toluene, at room temperature or by heating.

The compounds of formula VIII can be obtained by reaction of a compound of formula XIV with a compound of formula XV, as shown in the following scheme:

wherein W, R₃ and R₅ have the meaning previously described in relation with a compound of formula I or II.

The reaction between the compounds of formula XIV and XV may be carried out in the presence of a base such as diisopropylethylamine, diethylamine or triethylamine, in a suitable solvent such as THF or acetonitrile, and at a temperature comprised between −78° C. and room temperature.

The compounds of formula XIV and XV are commercial or may be easily obtained from commercial compounds using standard procedures.

Furthermore, some compounds of the present invention can also be obtained from other compounds of formula I or II by appropriate conversion reactions of functional groups in one or several steps, using well-known reactions in organic chemistry under the standard experimental conditions. Said transformations can be carried out for example upon R₃ and include, for example the substitution of a primary or secondary amine by treatment with an alkylating agent, the reaction of an acid or ester with an amine to obtain the corresponding amide, the conversion of an amine into a sulfonamide and the hydrolysis of an ester to obtain a carboxylic acid. In some of these conversions it may be necessary or advisable to protect the reactive or unstable groups by means of conventional protective groups.

As it will be obvious to those skilled in the art, these interconversion reactions can be carried out upon the compounds of formula I or II as well as upon any suitable synthesis intermediate thereof.

As mentioned above, the compounds of the present invention act by inhibiting JAK/STAT signaling pathways, particularly by inhibiting JAK3 activity. Therefore, the compounds of the invention are expected to be useful to treat or prevent diseases in which JAKs, particularly JAK3, play a role in mammals, including human beings. These diseases include, but are not limited to, transplant rejection; immune, autoimmune and inflammatory diseases; neurodegenerative diseases; and proliferative disorders (see e.g. O'Shea J. J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Cetkovic-Cvrlje M. et al, Arch. Immunol. Ther. Exp. (Warsz), 2004, 52(2):68-82).

Acute or chronic transplant rejection reactions that can be treated or prevented with the compounds of the present invention include any kind of cell, tissue or organ xenotransplants or allografts, such as of heart, lung, liver, kidney, pancreas, uterus, joints, pancreatic islets, bone marrow, limbs, cornea, skin, hepatocytes, pancreatic beta cells, pluripotential cells, neuronal cells and myocardial cells, as well as graft-versus-host reactions (see e.g. Rousvoal G. et al, Transpl. Int. 2006, 19(12):1014-21; Borie D C. et al, Transplantation 2005, 79(7):791-801; Paniagua R. et al, Transplantation 2005, 80(9):1283-92; Higuchi T. et al, J. Heart Lung Transplant. 2005, 24(10):1557-64; Säemann M D. et al, Transpl Int. 2004, 17(9):481-89; Silva Jr H T. et al, Drugs 2006, 66(13):1665-1684).

Immune, autoimmune or inflammatory diseases that can be treated or prevented with the compounds of the present invention include among others, rheumatic diseases (e.g. rheumatoid arthritis and psoriatic arthritis), autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, and neutropenia), autoimmune gastritis and inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), scleroderma, type I diabetes and complications from diabetes, type B hepatitis, type C hepatitis, primary biliary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, eczema, skin sunburns, suppression of HIV replication, infertility of autoimmune origin, autoimmune thyroid disease (Grave's disease), interstitial cystitis, mast cell-mediated allergic reactions such as asthma, angiodema, anaphylaxis, bronchitis, rhinitis and sinusitis, and inflammatory or autoimmune ocular diseases such as dry eye syndrome, glaucoma, Sjögren's syndrome, uveitis and retinopathy of prematurity (see e.g. Sorbera L A. et al, Drugs of the Future 2007, 32(8):674-680; O'Shea J. J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Muller-Ladner U. et al, J. Immunol. 2000, 164(7): 3894-3901; Walker J G. et al, Ann. Rheum. Dis. 2006, 65(2):149-56; Millci A J. et al, Arthritis Rheum. 2006, 54 (9, Suppl): abstr 789; Kremer J M. et al, Arthritis Rheum. 2006, 54, 4116, presentation no. L40; Cetkovic-Cvrlje M. et al, Arch Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82; Malaviya R. et al, J. Pharmacol. Exp. Ther. 2000, 235(3):912-26; Malaviya R. et al, J. Biol. Chem. 1999, 274(38):27028-38; Wilkinson B et al, Ann. Rheum. Dis. 2007, 66(Suppl 2): Abst. THU0099; Matsumoto M. et al, J. Immunol. 1999, 162(2):1056-63, West K., Curr Opin Inventig Drugs 2009:10(5):491-504, Huang Y. et al., Exp Eye res 2007:85(5):684-95, Killedar S Y et al, Laboratory Investigation 2006:86:1243-1280, Egwuagu C. E., Cytokine 2009:47(3):149-156, Byfield G., Investigative Ophtalmology & Viral Science 2009:50:3360).

Neurodegenerative diseases that can be treated or prevented with the compounds of the present invention include, among others, amyotrophic lateral sclerosis and Alzheimer's disease (see e.g. Trieu V N. et al, Biochem. Biophys. Res. Commun. 2000, 267(1):22-5).

Proliferative disorders that can be treated or prevented with the compounds of the present invention include, among others, leukemias, lymphomas, glioblastoma multiforme, colon carcinoma, as well as thromboembolic and allergic complications associated with these diseases (see e.g. Sudbeck E A. et al, Clin. Cancer Res. 1999, 5(6):1569-82; Narla R K. et al, Clin. Cancer Res. 1998, 4(10):2463-71; Lin Q. et al, Am J. Pathol. 2005, 167(4):969-80; Tibbles H E. et al, J. Biol. Chem. 2001, 276(21):17815-22).

It has been found that certain compounds of formula I or II, besides inhibiting JAK3 activity, also inhibit JAK2 kinase to varying degrees, and therefore can also be useful for the treatment or prevention of any disease mediated by JAK2 kinase. A group of such JAK2-mediated diseases are myeloproliferative disorders, including polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome (see e.g. Geron I. et al, Cancer cell 2008, 13:321-330; Pardanani A. et al, Leukemia 2007, 21 (8):1658-68; Mathur A. et al, Biochem Pharmacol 2009, 78(4):382-9; Manshouri T. et al, Cancer Sci. 2008, 99(6):1265-73; Wernig G. et al, Cancer cell 2008, 13(4):311-20. Elizabeth O. et al, Blood, 111(12: 5663-5671).

Compounds of formula I or II wherein R₁ and R₂ are hydrogen have been found to be particularly useful as JAK2 inhibitors, and thus can be particularly useful, in addition to treating or preventing all the diseases mentioned in the preceding paragraphs, also for the treatment or prevention of myeloproliferative disorders (MPD).

Thus, another aspect of the invention relates to a compound of formula I or II, or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by JAK2. More preferably, the disease mediated by JAK2 is a myeloproliferative disorder. In a preferred embodiment, the compounds of formula I or II are those wherein R₁ and R₂ are hydrogen.

Another aspect of the present invention relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by JAK2. More preferably, the disease mediated by JAK2 is a myeloproliferative disorder. In a preferred embodiment, the compounds of formula I or II are those wherein R₁ and R₂ are hydrogen.

Another aspect of the present invention relates to a method of treating or preventing a disease mediated by JAK2 in a subject in need thereof, especially a human being, which comprises administering to said subject a compound of formula I or II, or a pharmaceutically acceptable salt thereof. More preferably, the disease mediated by JAK2 is a myeloproliferative disease. In a preferred embodiment, the compounds of formula I or II are those wherein R₁ and R₂ are hydrogen

Another aspect of the invention relates to a compound of formula I or II, or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a myeloproliferative disorder. In a preferred embodiment, the myeloproliferative disorder is selected from polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome. In a preferred embodiment, the compounds of formula I or II are those wherein R₁ and R₂ are hydrogen.

Another aspect of the invention relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a myeloproliferative disorder. In a preferred embodiment, the myeloproliferative disorder is selected from polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome. In a preferred embodiment, the compounds of formula I or II are those wherein R₁ and R₂ are hydrogen.

Another aspect of the present invention relates to a method of treating or preventing a myeloproliferative disorder in a subject in need thereof, especially a human being, which comprises administering to said subject a compound of formula I or II or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the myeloproliferative disorder is selected from polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome. In a preferred embodiment, the compounds of formula I or II are those wherein R₁ and R₂ are hydrogen.

Biological assays that can be used to determine the ability of a compound to inhibit JAKs, particularly JAK3 and JAK2, are well known in the art. For example, a compound to be tested can be incubated in the presence of the desired JAK, such as JAK3 or JAK2, to determine whether inhibition of JAK enzymatic activity occurs, as described in the assay of examples 38 and 39 for JAK3 and JAK2, respectively. Other in vitro useful assays that can be used to measure JAK3-inhibitory activity include cellular assays, for example IL-2-induced proliferation of human T lymphocytes. The immunosuppressive activity of the compounds of the invention can be tested using standard in vivo animal models for immune and autoimmune diseases, which are well known in the art. For example, the following assays can be used: delayed-type hypersensitivity (DTH) (see e.g. the method disclosed in Kudlacz E. et al, Am J. Transplant. 2004, 4(1):51-7, the contents of which are incorporated herein by reference), rheumatoid arthritis models such as collagen-induced arthritis (see e.g. the method disclosed in Holmdahl R et al, APMIS, 1989, 97(7):575-84, the contents of which are incorporated herein by reference), multiple sclerosis models such as experimental autoimmune encephalomyelitis (EAE) (see e.g. the method disclosed in González-Rey et al, Am. J. Pathol. 2006, 168(4): 1179-88, the contents of which are incorporated herein by reference) and transplant rejection models (see e.g. the various animal models disclosed in the references listed above in relation to the treatment of transplant rejection, incorporated herein by reference). The antiproliferative activity of the compounds of the invention can be tested using standard in vivo animal models well known in the art, such as xenograft studies (see e.g Mohammad R H. et al, Pancreas. 1998; 16(1):19).

For selecting active compounds for JAK3, testing at 10 μM must result in an activity of more than 50% inhibition of JAK3 activity in the test provided in example 38. More preferably, when tested in this assay compounds should exhibit more than 50% inhibition at 1 μM, and still more preferably, they should exhibit more than 50% inhibition at 0.1 μM.

For selecting active compounds for JAK2, testing at 10 μM must result in an activity of more than 50% inhibition of JAK2 activity in the test provided in example 39 More preferably, when tested in this assay compounds should exhibit more than 50% inhibition at 1 μM, and still more preferably, they should exhibit more than 50% inhibition at 0.1 μM.

Assays that can be used to predict the PK profile of a compound are well known in the art. For example, a Caco-2 assay can be used to determine in vitro the potential for oral absorption of a compound. To show a good PK profile the compound must also exhibit a suitable clearance, as determined in a standard test using for example human liver microsomes in an assay such as the one described in example 40.

Standard assays can be used to assess potential toxic effects of drug candidates, all of which are well known in the art. Such tests include e.g. viability assays in different cell lines such as human hepatocyte carcinoma cells (Hep G2), which can be performed following standard procedures, such as the one described in example 41.

The present invention also relates to a pharmaceutical composition that comprises a compound of the present invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. The excipients must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

The compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as it is well known, will depend upon the nature of the active compound and its route of administration. Any route of administration may be used, for example oral, parenteral, nasal, ocular, rectal and topical administration.

Solid compositions for oral administration include tablets, granulates and capsules. In any case the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with excipients. These excipients can be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogenphosphate; binding agents such as for example starch, gelatin or povidone; disintegrants such as sodium carboxymethyl starch or sodium croscarmellose; and lubricating agents such as for example magnesium stearate, stearic acid or talc. Tablets can be additionally coated with suitable excipients by using known techniques with the purpose of delaying their disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, or simply to improve their organoleptic properties or their stability. The active compound can also be incorporated by coating onto inert pellets using natural or synthetic film-coating agents. Soft gelatin capsules are also possible, in which the active compound is mixed with water or an oily medium, for example coconut oil, mineral oil or olive oil.

Powders and granulates for the preparation of oral suspensions by the addition of water can be obtained by mixing the active compound with dispersing or wetting agents; suspending agents and preservatives. Other excipients can also be added, for example sweetening, flavoring and colouring agents.

Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, such as purified water, ethanol, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol. Said compositions can also contain coadjuvants such as wetting, suspending, sweetening, favoring agents, preservatives and buffers.

Injectable preparations, according to the present invention, for parenteral administration, comprise sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils. These compositions can also contain coadjuvants, such as wetting, emulsifying, dispersing agents and preservatives. They may be sterilized, by any known method or prepared as sterile solid compositions, which will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile materials and keep them under these conditions throughout all the manufacturing process.

For the rectal administration, the active compound can be preferably formulated as a suppository on an oily base, such as for example vegetable oils or solid semisynthetic glycerides, or on a hydrophilic base such as polyethylene glycols (macrogol).

The compounds of the invention can also be formulated for their topical application for the treatment or prevention of pathologies occurring in zones or organs accessible through this route, such as eyes, skin and the intestinal tract. Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients.

For the nasal administration or for inhalation, the compound can be formulated as an aerosol and it can be conveniently released using suitable propellants.

The dosage and frequency of doses will depend upon the nature and severity of the disease to be treated, the age, the general condition and body weight of the patient, as well as the particular compound administered and the route of administration, among other factors. A representative example of a suitable dosage range is from about 0.01 mg/Kg to about 100 mg/Kg per day, which can be administered as a single or divided doses.

The following examples illustrate the scope of the invention.

EXAMPLES

The following abbreviations have been used in the examples:

-   AcOH: acetic acid -   AcN: acetonitrile -   DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene -   DIPEA: N,N-diisopropylethylamine -   DMAC: N,N-dimethylacetamide -   DMF: N,N-dimethylformamide -   EDC: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide -   EtOAc: ethyl acetate -   EtOH: ethanol -   HATU: 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium     hexafluorophosphate Methanaminium -   HOBt: 1-hydroxybenzotriazole -   HPLC: high performance liquid chromatography -   LC-MS: liquid chromatography-mass spectroscopy -   MeI: iodomethane -   MeOH: methanol -   PTSA: para-toluene sulfonic acid -   TBAF: tetrabutylammonium fluoride -   TBME: tert-butyl methyl ether -   TEA: triethylamine -   TFA: trifluoroacetic acid -   THF: tetrahydrofurane -   TLC: thin layer cromatography -   t_(R): retention time

One of the following methods was used to determine the LC-MS spectrums:

-   Method 1: Column SunFire C18 3.5 μm, (100 mm×2.1), flow rate: 0.3     mL/min, eluent A=CH3CN:MeOH 1:1 B═NH₄Ac 5 mM pH 7, gradient: 0 min     10% A; 17 min 95% A; 10 min 95% A. -   Method 2: Column XBridge, 3.5 μm (50 mm×4.6), temperature: 30° C.,     flow rate: 2 mL/min, eluent A=NH₄HCO₃ 10 mM (pH=9), B═AcN, gradient:     0 min 5% B; 4.8 min 100% B; -   Method 3: Column XBridge, 3.5 μm (50 mm×4.6), temperature: 50° C.,     flow rate: 1.6 mL/min, eluent A=NH₄HCO₃ 10 mM (pH=9), B═AcN,     gradient: 0 min 5% B; 3.5 min 1005% B; -   Method 4 (Palau): Column Waters Acquity UPLC BEH C18 (1.7 μm, 2.1     mm×50 mm), temperature: 40° C., flow: 0.5 mL/min, eluent: ACN     (A)/ammonium bicarbonate 10 mM (B), gradient: 0 min 10% A=3.75 min     90% A -   Method 5: Column YMC, 3.5 μm (50 mm×4.6), temperature: 50° C., flow     rate: 1.3 mL/min, eluent A=H₂O (0.1% HCOOH), B═AcN (0.1% HCOOH),     gradient: 0 min 5% B; 3.5 min 100% B.

Reference Example 1 1-Amino-4-trifluoromethylpyridinium 2,4,6-trimethylbenzenesulfonate

To a solution of 4-trifluoromethylpyridine (2.23 g, 15.2 mmol) in CH₂Cl₂ (66 mL) at 0° C., O-(mesitylsulfonyl)hydroxylamine (3.27 g, 15.2 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was filtered to afford the desired product with quantitative yield.

LC-MS (method 4); t_(R)=1.07 min; m/z=199 (MH⁺),

Reference Example 2 (S)-3-(4-(1-Acetylpiperidin-3-ylamino)-5-aminopyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Following a similar procedure to that described in example 1 (section a to d), but using (S)-1-acetyl-3-aminopiperidine instead of tetrahydro-2H-pyran-4-amine, the desired compound was obtained.

LC-MS (method 3): t_(R)=1.59 min; m/z=377 (MH⁺).

Following a similar procedure to that described in reference example 2, but using in each case the corresponding starting materials, the following compounds were obtained:

Reference HPLC t_(R) example Name Starting Materials method (min) m/z 2a (S)-tert-butyl 3-(5-amino-2-(5- 1-amino-4- 3 2.32 424 methylpyrazolo[1,5-a]pyridin-3- methylpyridinium yl)pyrimidin-4-ylamino)piperidine-1- 2,4,6- carboxylate trimethylbenzenesulfonate(1),, (S)-3-amino- (1-tert- butoxycarbonyl)piperidine and 2,4-dichloro-5- nitropyrimidine 2b tert-butyl 4-(5-amino-2-(pyrazolo[1,5- 1-aminopyridinium 4 2.00 410 a]pyridin-3-yl)pyrimidin-4- iodide,, 4-amino-(1- ylamino)piperidine-1-carboxylate tert- butoxycarbonyl)piperidine and 2,4-dichloro-5- nitropyrimidine 2c 2-(pyrazolo[1,5-a]pyridin-3-yl)-N4- 1-aminopyridinium 3 1.55 311 (tetrahydro-2H-pyran-4-yl)pyrimidine- iodide, tetrahydro-2H- 4,5-diamine pyran-4-amine and 2,4-dichloro-5- nitropyrimidine 2d (S)-tert-butyl 3-(3-amino-6- 1-aminopyridinium 3 2.43 409 (pyrazolo[1,5-a]pyridin-3-yl)pyridin-2- iodide, (S)-3-amino- ylamino)piperidine-1-carboxylate (1-tert- butoxycarbonyl)piperidine and 2,6-dichloro-3- nitropyridine 2e 3-(5-amino-4-(8-fluorochroman-4- 1-amino-4- 1 9.28 402 ylamino)pyrimidin-2-yl)pyrazolo[1,5- cyanopyridinium 2,4,6- a]pyridine-5-carbonitrile trimethylbenzenesulfonate, 8-fluorochroman- 4-amine and 2,4- dichloro-5- nitropyrimidine 2f (S)-3-(6-(1-acetylpiperidin-3-ylamino)- 1-amino-4- 3 1.58 377 5-aminopyridin-2-yl)pyrazolo[1,5- cyanopyridinium 2,4,6- a]pyridine-5-carbonitrile trimethylbenzenesulfonate, (S)-1-acetyl-3- aminopiperidin and 2,6-dichloro-3- nitropyridine 2g 6-(pyrazolo[1,5-a]pyridin-3-yl)-N2- 1-aminopyridinium 5 1.68 310 (tetrahydro-2H-pyran-4-yl)pyridine- iodide, tetrahydro-2H- 2,3-diamine pyran-4-amine and 2,6-dichloro-3- nitropyridine 2h (S)-tert-butyl 3-(3-amino-6-(5- 1-amino-4- 3 2.50 434 cyanopyrazolo[1,5-a]pyridin-3- cyanopyridinium 2,4,6- yl)pyridin-2-ylamino)piperidine-1- trimethylbenzenesulfonate, carboxylate (S)-3-amino-(1- tert- butoxycarbonyl)piperidine and 2,6-dichloro-3- nitropyridine 2i 3-(5-amino-4-(trans-4- 1-amino-4- 3 1.45 350 hydroxycyclohexylamino)pyrimidin-2- cyanopyridinium 2,4,6- yl)pyrazolo[1,5-a]pyridine-5- trimethylbenzenesulfonate, carbonitrile trans-4- aminocyclohexanol and 2,6-dichloro-3- nitropyridine. (1) described by Zhang et al Journal of Heterocyclic Chemistry: 44; 4; 2007; 919-922

Example 1 3-(8-Oxo-9-tetrahydro-2H-pyran-4-yl-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile a) 2-Chloro-5-nitro-N-tetrahydro-2H-pyran-4-ylpyrimidin-4-amine

To a solution of 2,4-dichloro-5-nitropyrimidine (1.03 g, 5.15 mmol) in THF (40 mL) at −78° C., DIPEA (2.0 mL, 11.86 mmol) and tetrahydro-2H-pyran-4-amine (0.54 mL, 5.15 mmol) were added. The reaction mixture was stirred from −78 to −50° C. for 5 h. The crude mixture was quenched with H₂O (50 mL), extracted with EtOAc (3×40 mL) and the combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using EtOAc/hexanes mixtures of increasing polarity as eluent, to afford 1.04 g of the desired compound (78% yield).

b) 5-Nitro-N-(tetrahydro-2H-pyran-4-yl)-2-[(trimethylsilyl)ethynyl]pyrimidin-4-amine

To a suspension of the compound obtained in the previous section (1.01 g. 3.90 mmol), Pd(PPh₃)₂Cl₂ (137 mg, 0.19 mmol) and CuI (37 mg. 0.19 mmol) in toluene (40 mL), TEA (1.6 mL, 11.7 mmol) and trimethylsilylacetylene (0.7 mL, 5.07 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, quenched with saturated NH₃Cl aqueous solution (70 mL) and extracted with EtOAc (3×40 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The crude residue was cromatographed on a silica gel flash system (SP1 Biotage) using EtOAc/hexanes mixtures of increasing polarity as eluent to afford 0.96 g of the desired product (77% yield).

c) 3-[5-Nitro-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile

To a suspension of the compound obtained in the previous section (500 mg, 1.56 mmol) and 1-amino-4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate (498 mg, 1.56 mmol) in AcN (30 mL), at 0° C., 1 M TBAF solution in THF (1.56 mL, 1.56 mmol) and a solution of DBU (0.47 mL, 3.12 mmol) in AcN (10 mL) were added. The reaction mixture was stirred at 0° C. for 5 min and 3 h at room temperature. The reaction mixture was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using EtOAc/hexanes mixtures of increasing polarity as eluent, to afford 227 mg of the desired compound (48% yield).

d) 3-[5-Amino-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile

A mixture of the compound obtained in the previous section (119 mg, 0.32 mmol) in EtOH (12 mL) was hydrogenated with Pt/C 5% (148 mg, 0.02 mmol) as a catalyst in the presence of thiophene in DIPEA (4% v/v, 9 drops). The reaction mixture was stirred under H₂ (g) atmosphere at room temperature for 1.5 h. The reaction mixture was filtered through a plug of Celite® and the solvent was concentrated off to afford 78 mg of the desired product (71% yield).

e) 3-(8-Oxo-9-tetrahydro-2H-pyran-4-yl-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of the compound obtained in the previous section (78 mg, 0.23 mmol) in THF (7 mL), 1,1′-carbonyldiimidazole (188 mg, 1.16 mmol) was added. The reaction mixture was stirred at room temperature for 4 h, quenched with saturated NaCl aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using MeOH/CH₂Cl₂ mixtures of increasing polarity as eluent, to afford 5.1 mg of the desired compound (61% yield).

LC-MS (method 1): t_(R)=14.25 min; m/z=362 (MH⁺).

Following a similar procedure to that described in example 1, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) Example Name Starting Material method (min) m/z 1a methyl (2R)-2-[2-(5- D-alanine methyl ester 1 14.48 364 cyanopyrazolo[1,5-a]pyridin-3-yl)-8- hydrochloride oxo-7,8-dihydro-9H-purin-9- yl]propanoate 1b (S)-tert-butyl 3-(2-(5- (S)-tert-butyl 3- 2 2.23 461 cyanopyrazolo[1,5-a]pyridin-3-yl)-8- aminopiperidine-1- oxo-7H-purin-9(8H)-yl)piperidine-1- carboxylate carboxylate 1c (R)-tert-butyl 3-(2-(5- (R)-tert-butyl 3- 2 2.23 461 cyanopyrazolo[1,5-a]pyridin-3-yl)-8- aminopiperidine-1- oxo-7H-purin-9(8H)-yl)piperidine-1- carboxylate carboxylate 1d (S)-3-(9-(1-methoxypropan-2-yl)-8- (S)-1-methoxypropan- 2 1.82 350 oxo-8,9-dihydro-7H-purin-2- 2-amine yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 1e 3-(9-(4,4-difluorocyclohexyl)-8-oxo- 4,4- 2 2.03 396 8,9-dihydro-7H-purin-2- difluorocyclohexanamine yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 1f 3-(9-(1,1-dioxotetrahydrothien-3-yl)-8- 3-amino-1,1- 2 1.43 396 oxo-8,9-dihydro-7H-purin-2- dioxotetrahydrothiophene yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 1g 3-(9-(2-fluorobenzyl)-8-oxo-8,9- 2-fluorobenzylamine 1 16.58 386 dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 1h 3-(9-(4-methoxybut-1-yl)-8-oxo-8,9- 4-methoxybutan-1- 1 15.15 396 dihydro-7H-purin-2-yl)pyrazolo[1,5- amine a]pyridine-5-carbonitrile 1i methyl (2S)-2-[2-(5- L-alanine methyl ester 3 1.83 436 cyanopyrazolo[1,5-a]pyridin-3-yl)-8- hydrochloride oxo-7,8-dihydro-9H-purin-9- yl]propanoate 1j 9-(1-acetylpiperidin-4-yl)-2-(5- 1-acetyl-4- 4 1.68 446 (trifluoromethyl)pyrazolo[1,5-a]pyridin- aminopiperidine 3-yl)-7H-purin-8(9H)-one(1) hydrochloride 1k (S)-tert-butyl 3-(2-(5- (S)-tert-butyl 3- 5 2.72 447 cyanopyrazolo[1,5-a]pyridin-3-yl)-8- aminopyrrolidine-1- oxo-7H-purin-9(8H)-yl)pyrrolidine-1- carboxylate carboxylate 1l (R)-tert-butyl 3-(2-(5- (R)-tert-butyl 3- 3 2.25 447 cyanopyrazolo[1,5-a]pyridin-3-yl)-8- aminopyrrolidine-1- oxo-7H-purin-9(8H)-yl)pyrrolidine-1- carboxylate carboxylate 1m (S)-tert-butyl 3-(2-(5- (S)-tert-butyl 3- 3 2.47 450 methylpyrazolo[1,5-a]pyridin-3-yl)-8- aminopiperidine-1- oxo-7H-purin-9(8H)-yl)piperidine-1- carboxylate carboxylate (2) 1n ethyl 2-(2-(5-cyanopyrazolo[1,5- ethyl 2-aminoacetate 3 1.82 364 a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)- yl)acetate 1o 3-(9-(trans-4-hydroxycyclohexyl)-8- trans-4- 3 1.55 376 oxo-8,9-dihydro-7H-purin-2- aminocyclohexanol yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 1p 3-(9-(8-fluorochroman-4-yl)-8-oxo-8,9- 8-fluorochroman-4- 1 15.43 428 dihydro-7H-purin-2-yl)pyrazolo[1,5- amine a]pyridine-5-carbonitrile 1q tert-butyl 4-(2-(5-cyanopyrazolo[1,5- tert-butyl 4- 3 2.33 461 a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)- aminopiperidine-1- yl)piperidine-1-carboxylate carboxylate 1r tert-butyl 3-(2-(5-cyanopyrazolo[1,5- tert-butyl 3- 3 2.20 433 a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)- aminoazetidine-1- yl)azetidine-1-carboxylate carboxylate 1s 9-(1-acetylpiperidin-4-yl)-2-(5- 1-acetyl-4- 4 1.38 392 methylpyrazolo[1,5-a]pyridin-3-yl)-7H- aminopiperidine purin-8(9H)-one (2) hydrochloride (1) step c) was performed using reference example 1 instead of 1-amino-4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate (2) step c) was performed using 1-amino-4-methylpyridinium 2,4,6-trimethylbenzenesulfonate (described by Zhang et al Journal of Heterocyclic Chemistry; 44; 4; 2007; 919-922) instead of 1-amino-4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate

Example 2 3-(2-Oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile a) 6-Chloro-3-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine

To a suspension of 2,6-dichloro-3-nitropyridine (6 g, 31.1 mmol) in AcN (200 mL) at 0° C., TEA (9 mL, 62.2 mmol) and tetrahydro-2H-pyran-4-amine (3.15 g. 31.1 mmol) were added. The reaction mixture was stirred at 0° C. for 1.5 h. The reaction crude was tempered and stirred at room temperature for 18 h. The reaction mixture was evaporated under reduced pressure, dissolved in EtOAc, and washed thrice with saturated NaHCO₃ aqueous solution. The combined organic phases were dried over MgSO₄ and concentrated to dryness. The crude residue was cromategraphed on a silica gel flash system (ISCO Combiflash) using hexanes/TBME mixtures of increasing polarity as eluent to afford 5.23 g of the desired product (65% yield).

b) 3-Nitro-N-(tetrahydro-2H-pyran-4-yl)-6-((trimethylsilyl)ethynyl)pyridin-2-amine

Following a similar procedure to that described in example 1, section b, but using the compound obtained in previous section as starting material, the desired compound was obtained (87% yield).

c) 3-(5-Nitro-6-(tetrahydro-2H-pyran-4-ylamino)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Following a similar procedure to that described in example 1, section c, but using the compound obtained in previous section as starting material, the desired compound was obtained (16% yield).

d) 3-(5-Amino-6-(tetrahydro-2H-pyran-4-ylamino)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Following a similar procedure to that described in example 1, section d, but using the compound obtained in previous section as starting material, the desired compound was obtained (19% yield).

e) Title Compound

Following a similar procedure to that described in example 1, section e, but using the compound obtained in previous section as starting material, the desired compound was obtained (23% yield).

LC-MS (method 3): t_(R)=1.83 min; m/z=361 (MH⁺)

Following a similar procedure to that described in example 2, but using in each case the corresponding starting materials, the following compounds ware obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 2a (S)-tert-butyl 3-(2-oxo-5- (S)-3-amino-(1-tert- 3 2.47 435 (pyrazolo[1,5-a]pyridin-3-yl)-1H- butoxycarbonyl)piperidine imidazo[4,5-b]pyridin-3(2H)- and 1- yl)piperidine-1-carboxylate aminopyridinium iodide 2b (R)-tert-butyl 3-(2-oxo-5- (R)-tert-butyl 3- 3 2.27 421 (pyrazolo[1,5-a]pyridin-3-yl)-1H- aminopyrrolidine-1- imidazo[4,5-b]pyridin-3(2H)- carboxylate and 1- yl)pyrrolidine-1-carboxylate aminopyridinium iodide 2c (S)-tert-butyl 3-(2-oxo-5- (S)-tert-butyl 3- 3 2.27 421 (pyrazolo[1,5-a]pyridin-3-yl)-1H- aminopyrrolidine-1- imidazo[4,5-b]pyridin-3(2H)- carboxylate and 1- yl)pyrrolidine-1-carboxylate aminopyridinium iodide 2d (S)-tert-butyl 3-(5-(5- (S)-3-amino-(1-tert- 3 2.50 434 cyanopyrazolo[1,5-a]pyridin-3-yl)-2- butoxycarbonyl)piperidine oxo-1H-imidazo[4,5-b]pyridin- and 3(2H)-yl)piperidine-1-carboxylate 1-amino-4- cyanopyridinium 2,4,6- trimethylbenzenesulfonate 2e 5-(pyrazolo[1,5-a]pyridin-3-yl)-3- tetrahydro-2H-pyran-4- 3 1.80 336 (tetrahydro-2H-pyran-4-yl)-1H- amine and 1- imidazo[4,5-b]pyridin-2(3H)-one aminopyridinium iodide 2f (R)-tert-butyl 3-(2-oxo-5- (R)-3-amino-(1-tert- 4 2.15 435 (pyrazolo[1,5-a]pyridin-3-yl)-1H- butoxycarbonyl)piperidine imidazo[4,5-b]pyridin-3(2H)- and 1- yl)piperidine-1-carboxylate aminopyridinium iodide

Example 3 2-(Pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one

Following a similar procedure to that described in example 1, but using 1-aminopyridinium iodide instead of 1-amino-4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate, the desired compound was obtained (84% yield).

LC-MS (method 3): t_(R)=1.62 min; m/z=337 (MH⁺).

Following a similar procedure to that described in example 3, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 3a 2-(pyrazolo[1,5-a]pyridin-3-yl)-9- (tetrahydro-2H-pyran- 2 1.63 351 ((tetrahydro-2H-pyran-4-yl)methyl)- 4-yl)methanamine 7H-purin-8(9H)-one 3b (S)-tert-butyl 3-(8-oxo-2- (S)-tert-butyl-3- 2 2.33 436 (pyrazolo[1,5-a]pyridin3-yl)-7H- aminopiperidine-1- purin-9(8H)-yl)piperidine-1- carboxylate carboxylate 3c 9-(2-methoxyethyl)-2-(pyrazolo[1,5- 2-methoxyethylamine 2 1.55 311 a]pyridin-3-yl)-7H-purin-8(9H)-one 3d 9-(8-fluorochroman-4-yl)-2- 8-fluorochroman-4- 1 16.07 403 (pyrazolo[1,5-a]pyridin-3-yl)-7H- amine purin-8(9H)-one 3e methyl (2S)-2-(8-oxo-2- L-alanine methyl ester 3 1.73 339 (pyrazolo[1,5-a]pyridin-3-yl)-7,8- hydrochloride dihydro-9H-purin-9-yl)propanoate 3f (S)-tert-butyl 3-(8-oxo-2- (S)-tert-butyl 3- 3 2.13 422 (pyrazolo[1,5-a]pyridin-3-yl)-7H- aminopyrrolidine-1- purin-9(8H)-yl)pyrrolidine-1- carboxylate carboxylate 3g tert-butyl 4-(8-oxo-2-(pyrazolo[1,5- tert-butyl 4- 3 2.35 461 a]pyridin-3-yl)-7H-purin-9(8H)- aminopiperidine-1- yl)piperidine-1-carboxylate carboxylate 3h 9-(1-methylpiperidin-4-yl)-2- 1-methylpiperidin-4- 4 1.38 350 (pyrazolo[1,5-a]pyridin-3-yl)-7H- amine purin-8(9H)-one 3i 5-(pyrazolo[1,5-a]pyridin-3-yl)-3- 2,2,6,6- 4 1.48 391 (2,2,6,6-tetramethylpiperidin-4-yl)- tetramethylpiperidin-4- 1H-imidazo[4,5-b]pyridin-2(3H)-one amine

Example 4 3-(7-Methyl-8-oxo-9-tetrahydro-2H-pyran-4-yl-8,9-dihydro-7H-purin-2yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of example 1 (48 mg, 0.13 mmol) in DMF (6 mL), 55-65% NaH dispersion in mineral oil (7.3 mg, 0.18 mmol) was added and the resulting solution was stirred at room temperature for 10 min. Then MeI (0.015 mL, 0.25 mmol) was added and the reaction mixture was stirred for 15 h at room temperature. The reaction mixture was quenched with saturated NaCl aqueous solution (10 mL) and extracted with EtOAc (3×10 mL) and CH₂Cl₂ (2×10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using MeOH/CH₂Cl₂ mixtures of increasing polarity as eluent, to afford 50 mg of the desired compound (quantitative yield).

LC-MS (method 1): t_(R)=15.48 min; m/z=376 (MH⁺).

Following a similar procedure to that described in example 4, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) Example Name Starting Material method (min) m/z 4a (S)-tert-butyl 3-(2-(5- Example 1b 2 3.22 475 cyanopyrazolo[1,5-a]pyridin-3-yl)- 7-methyl-8-oxo-7H-purin-9(8H)- yl)piperidine-1-carboxylate 4b (R)-tert-butyl 3-(2-(5- Example 1c 2 3.22 475 cyanopyrazolo[1,5-a]pyridin-3-yl)- 7-methyl-8-oxo-7H-purin-9(8H)- yl)piperidine-1-carboxylate 4c 9-(8-fluorochroman-4-yl)-7- Example 3d 1 16.83 417 methyl-2-(pyrazolo[1,5-a]pyridin- 3-yl)-7H-purin-8(9H)-one

Example 5 (S)-tert-Butyl 3-(7-methyl-8-oxo-2-(pyrazolo[1,5-a]pyridine-3-yl)-7H-purin-9(8H)-yl)piperidine-1-carboxylate

To a solution of example 3b (70 mg, 0.160 mmol) in DMF (3.5 mL), at 0° C. ¹BuOK (27 mg, 0.24 mmol) and MeI (0.019 mL, 0.32 mmol) were added. The reaction mixture was stirred at room temperature for 20 min and evaporated to dryness. The crude residue was chromatographed on a silica gel flash system (ISCO Rf) using CH₂Cl₂/MeOH mixtures of increasing polarity as eluent to afford 64 mg of the desired product (89% yield).

LC-MS (method 3): t_(R)=2.58 min; m/z=450 (MH⁺).

Following a similar procedure to that described in example 5, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 5a 7-methyl-2-(pyrazolo[1,5-a]pyridin- example 3 2 1.83 351 3-yl)-9-(tetrahydro-2H-pyran-4-yl)- 7H-purin-8(9H)-one 5b 3-(1-methyl-2-oxo-3-(tetrahydro-2H- example 2 2 2.62 375 pyran-4-yl)-2,3-dihydro-1H- imidazo[4,5-b]pyridin-5- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 5c 9-(2-methoxyethyl)-7-methyl-2- Example 3c 2 1.77 325 (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one 5d 7-methyl-2-(pyrazolo[1,5-a]pyridin- Example 3a 2 1.87 365 3-yl)-9-[(tetrahydro-2H-pyran-4- yl)methyl]-7H-purin-8(9H)-one 5e 3-(9-(4,4-difluorocyclohexyl)-7- Example 1e 2 2.32 410 methyl-8-oxo-8,9-dihydro-7H-purin- 2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 5f 3-(9-(1,1-dioxotetrahydrothien-3-yl)- Example 1f 2 1.75 410 8,9-dihydro-7-methyl-8-oxopurin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile. 5g (S)-tert-butyl 3-(5-(5- Example 2d 2 2.54 474 cyanopyrazolo[1,5-a]pyridin-3-yl)-1- methyl-2-oxo-1H-imidazo[4,5- b]pyridin-3(2H)-yl)piperidine-1- carboxylate 5h 3-(9-(2-fluorobenzyl)-7-methyl-8- Example 1g 1 17.66 400 oxo-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 5i 9-(1-acetylpiperidin-4-yl)-7-methyl- Example 1j 4 1.85 460 2-(5-(trifluoromethyl)pyrazolo[1,5- a]pyridin-3-yl)-7H-purin-8(9H)-one 5j (S)-tert-butyl 3-(1-methyl-2-oxo-5- Example 2a 3 2.73 449 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)- yl)piperidine-1-carboxylate 5k (S)-tert-butyl 3-(2-(5- Example 1k 3 2.52 461 cyanopyrazolo[1,5-a]pyridin-3-yl)-7- methyl-8-oxo-7H-purin-9(8H)- yl)pyrrolidine-1-carboxylate 5l (R)-tert-butyl 3-(2-(5- Example 1l 3 2.50 461 cyanopyrazolo[1,5-a]pyridin-3-yl)-7- methyl-8-oxo-7H-purin-9(8H)- yl)pyrrolidine-1-carboxylate 5m (S)-tert-butyl 3-(7-methyl-8-oxo-2- Example 3f 3 2.40 436 (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-9(8H)-yl)pyrrolidine-1- carboxylate 5n (R)-tert-butyl 3-(1-methyl-2-oxo-5- Example 2b 3 2.50 435 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)- yl)pyrrolidine-1-carboxylate 5o (S)-tert-butyl 3-(1-methyl-2-oxo-5- Example 2c 5 2.98 436 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)- yl)pyrrolidine-1-carboxylate 5p (S)-tert-Butyl 3-(1-ethyl-2-oxo-5- Example 2a 4 2.57 463 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)- yl)piperidine-1-carboxylate (1) 5q tert-butyl 4-(7-methyl-8-oxo-2- Example 3g 3 2.68 475 (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-9(8H)-yl)piperidine-1- carboxylate 5r (S)-tert-butyl 3-(7-methyl-8-oxo-2- Example 3b 3 2.62 450 (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-9(8H)-yl)piperidine-1- carboxylate 5s 1-methyl-5-(pyrazolo[1,5-a]pyridin- Example 2e 3 2.02 350 3-yl)-3-(tetrahydro-2H-pyran-4-yl)- 1H-imidazo[4,5-b]pyridin-2(3H)-one 5t (R)-tert-butyl 3-(1-methyl-2-oxo-5- Example 2f 3 2.73 449 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)- yl)piperidine-1-carboxylate 5u tert-butyl 4-(2-(5- Example 1q 3 2.68 475 cyanopyrazolo[1,5-a]pyridin-3-yl)-7- methyl-8-oxo-7H-purin-9(8H)- yl)piperidine-1-carboxylate 5v tert-butyl 3-(2-(5- Example 1r 3 2.47 447 cyanopyrazolo[1,5-a]pyridin-3-yl)-7- methyl-8-oxo-7H-purin-9(8H)- yl)azetidine-1-carboxylate (1) ethyl iodide instead of methyl iodide as starting material.

Example 6

(S)-3-(8-Oxo-9-(piperidin-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile hydrochloride

To a solution of example 1b (45 mg, 0.10 mmol) in dioxane (3 mL), 4 M HCl solution in dioxane (2 mL, 8.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness to give 48 mg of the desired compound (100% yield).

LC-MS (method 2): t_(R)=1.73 min; m/z=361 (MH⁺).

Following a similar procedure to that described in example 6, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Compound name Starting material method (min) (MH⁺) 6a (R)-3-(8-oxo-9-(piperidin-3-yl)-8,9- Example 1c 2 1.73 361 dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile hydrochloride 6b (R)-3-(7-methyl-8-oxo-9-(piperidin- Example 4b 2 2.05 375 3-yl)-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 6c (S)-3-(7-methyl-8-oxo-9-(piperidin-3- Example 4a 2 2.05 375 yl)-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 6d 9-(piperidin-4-yl)-2-(pyrazolo[1,5- Example 3g 2 1.28 336 a]pyridin-3-yl)-7H-purin-8(9H)-one 6e (S)-3-(2-oxo-3-(piperidin-3-yl)-2,3- Example 2d 2 1.54 360 dihydro-1H-imidazo[4,5-b]pyridin-5- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 6f (S)-3-(1-methyl-2-oxo-3-(piperidin-3- Example 5g 2 1.68 374 yl)-2,3-dihydro-1H-imidazo[4,5- b]pyridin-5-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile hydrochloride 6g (S)-1-methyl-3-(piperidin-3-yl)-5- Example 5j 1 12.46 349 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one hydrochloride 6h (S)-3-(7-methyl-8-oxo-9-(pyrrolidin- Example 5k 3 1.62 361 3-yl)-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 6i (R)-3-(7-methyl-8-oxo-9-(pyrrolidin- Example 5l 3 1.62 361 3-yl)-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 6j (S)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Example 3f 3 1.23 322 (pyrrolidin-3-yl)-7H-purin-8(9H)-one hydrochloride 6k (S)-7-methyl-2-(pyrazolo[1,5- Example 5m 3 1.48 336 a]pyridin-3-yl)-9-(pyrrolidin-3-yl)-7H- purin-8(9H)-one hydrochloride 6l (S)-3-(8-oxo-9-(pyrrolidin-3-yl)-8,9- Example 1k 3 1.35 347 dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile hydrochloride (1) 6m (R)-1-methyl-5-(pyrazolo[1,5- Example 5n 3 1.57 335 a]pyridin-3-yl)-3-(pyrrolidin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one hydrochloride 6n (R)-5-(pyrazolo[1,5-a]pyridin-3-yl)-3- Example 2b 3 1.40 321 (pyrrolidin-3-yl)-1H-imidazo[4,5- b]pyridin-2(3H)-one hydrochloride (1) 6o (R)-3-(8-oxo-9-(pyrrolidin-3-yl)-8,9- Example 1l 3 1.33 347 dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile hydrochloride (1) 6p (S)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Example 2c 3 1.40 321 (pyrrolidin-3-yl)-7H-purin-8(9H)-one hydrochloride 6q (S)-1-methyl-5-(pyrazolo[1,5- Example 5o 3 1.57 335 a]pyridin-3-yl)-3-(pyrrolidin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one hydrochloride 6r (S)-2-(5-methylpyrazolo[1,5- Example 1m 3 1.57 350 a]pyridin-3-yl)-9-(piperidin-3-yl)-7H- purin-8(9H)-one hydrochloride 6s (S)-1-ethyl-3-(piperidin-3-yl)-5- Example 5p 4 1.56 363 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one hydrochloride 6t 7-methyl-9-(piperidin-4-yl)-2- Example 5q 4 1.23 350 (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one hydrochloride 6u (S)-7-methyl-9-(piperidin-3-yl)-2- Example 5r 3 1.67 350 (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one hydrochloride 6v (S)-9-(piperidin-3-yl)-2- Example 3b 3 1.43 336 (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one hydrochloride 6w (R)-1-methyl-3-(piperidin-3-yl)-5- Example 5t 3 1.77 349 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one 6x (S)-3-(piperidin-3-yl)-5- Example 2a 3 1.60 335 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one hydrochloride 6y 3-(7-methyl-8-oxo-9-(piperidin-4-yl)- Example 5u 3 1.67 375 8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 6z (S)-3-(3-(piperidin-3-yl)-3H- Example 18e 3 1.68 3.44 imidazo[4,5-b]pyridin-5- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 6aa (S)-3-(2-methyl-3-(piperidin-3-yl)- Example 18f 3 1.72 358 3H-imidazo[4,5-b]pyridin-5- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 6ab 3-(8-oxo-9-(piperidin-4-yl)-8,9- Example 1q 1 11.13 361 dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile (1) 6ac 3-(9-(azetidin-3-yl)-7-methyl-8-oxo- Example 5v 3 1.50 347 8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 6ad (S)-3-(piperidin-3-yl)-5- Example 18i 3 1.65 319 (pyrazolo[1,5-a]pyridin-3-yl)-3H- imidazo[4,5-b]pyridine hydrochloride 6ae (S)-2-methyl-3-(piperidin-3-yl)-5- Example 21m 3 1.48 333 (pyrazolo[1,5-a]pyridin-3-yl)-3H- imidazo[4,5-b]pyridine hydrochloride (1) reaction performed with TFA/CH₂Cl₂ instead of 4M HCl solution in dioxane, and washed with with saturated NaHCO₃ aqueous solution.

Example 7 (S)-3-(9-(1-(2-Cyanoacetyl)piperidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of the compound obtained in example 6 (45 mg, 0.095 mmol) in anhydrous DMF (3 mL), 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (69 mg, 0.38 mmol) and anhydrous TEA (0.09 mL, 0.665 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO₂ aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg₂SO₄, filtered and concentrated. The crude residue was flash chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 11.7 mg of the desired compound (29% yield).

LC-MS (method 2): t_(R)=1.93 min; m/z=428 (MH⁺).

Following a similar procedure to that described in example 7, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Compound name Starting material method (min) (MH⁺) 7a (R)-3-(9-(1-(2-cyanoacetyl)piperidin- Example 6a 2 1.93 428 3-yl)-8-oxo-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 7b (R)-3-(9-(1-(2-cyanoacetyl)piperidin- Example 6b 2 2.30 442 3-yl)-7-methyl-8-oxo-8,9-dihydro- 7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 7c (S)-3-(9-(1-(2-cyanoacetyl)piperidin- Example 6c 2 2.30 442 3-yl)-7-methyl-8-oxo-8,9-dihydro- 7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 7d 3-(9-(1-(2-cyanoacetyl)pyrrolidin-3- 3-(7-methyl-8-oxo-9- 2 1.68 428 yl)-7-methyl-8-oxo-8,9-dihydro-7H- (pyrrolidin-3-yl)-8,9- purin-2-yl)pyrazolo[1,5-a]pyridine-5- dihydro-7H-purin-2- carbonitrile yl)pyrazolo[1,5- a]pyridine-5- carbonitrile hydrochloride (1) 7e 3-(9-((1-(2-cyanoacetyl)piperidin-4- 3-(7-methyl-8-oxo-9- 2 1.80 456 yl)methyl)-7-methyl-8-oxo-8,9- (piperidin-4-ylmethyl)- dihydro-7H-purin-2-yl)pyrazolo[1,5- 8,9-dihydro-7H-purin- a]pyridine-5-carbonitrile 2-yl)pyrazolo[1,5- a]pyridine-5- carbonitrile hydrochloride (2) 7f (S)-3-oxo-3-(3-(8-oxo-2- Example 6v 2 2.05 403 (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-9(8H)-yl)piperidin-1- yl)propanenitrile 7g (S)-3-(3-(7-methyl-8-oxo-2- Eample 6u 2 2.58 417 (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-9(8H)-yl)piperidin-1-yl)-3- oxopropanenitrile 7h (S)-3-(3-(1-(2-cyanoacetyl)piperidin- Example 6e 2 1.64 427 3-yl)-2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-5- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 7i (S)-3-(3-(1-methyl-2-oxo-5- Example 6g 5 1.95 416 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)- yl)piperidin-1-yl)-3-oxopropanenitrile 7j 3-(9-(1-(2-cyanoacetyl)azetidin-3- Example 6ac 2 2.10 414 yl)-7-methyl-8-oxo-8,9-dihydro-7H- purin-2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 7k (S)-3-(3-(2-(5-methylpyrazolo[1,5- Example 6r 3 1.73 417 a]pyridin-3-yl)-8-oxo-7H-purin- 9(8H)-yl)piperidin-1-yl)-3- oxopropanenitrile 7l (S)-3-(3-(1-ethyl-2-oxo-5- Example 6s 4 1.87 430 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)- yl)piperidin-1-yl)-3-oxopropanenitrile 7m 3-oxo-3-(4-(8-oxo-2-(pyrazolo[1,5- Example 6d 4 1.32 403 a]pyridin-3-yl)-7H-purin-9(8H)- yl)piperidin-1-yl)propanenitrile 7n (S)-3-(3-(1-(2-cyanoacetyl)piperidin- Example 6f 3 2.02 441 3-yl)-1-methyl-2-oxo-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-5- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 7o (R)-3-(3-(1-methyl-2-oxo-5- Example 6w 4 1.71 416 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)- yl)piperidin-1-yl)-3-oxopropanenitrile 7p (S)-3-oxo-3-(3-(2-oxo-5- Example 6x 3 1.75 402 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)- yl)piperidin-1-yl)propanenitrile 7q 3-(9-(1-(2-cyanoacetyl)piperidin-4- Example 6y 3 1.82 442 yl)-7-methyl-8-oxo-8,9-dihydro-7H- purin-2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 7r (S)-3-(3-(1-(2-cyanoacetyl)piperidin- Example 6z 5 2.20 411 3-yl)-3H-imidazo[4,5-b]pyridin-5- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 7s (S)-3-(3-(1-(2-cyanoacetyl)piperidin- Example 6aa 5 2.09 425 3-yl)-2-methyl-3H-imidazo[4,5- b]pyridin-5-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 7t (S)-3-(3-(2-methyl-5-(pyrazolo[1,5- Example 6ae 3 1.85 400 a]pyridin-3-yl)-3H-imidazo[4,5- b]pyridin-3-yl)piperidin-1-yl)-3- oxopropanenitrile 7u (S)-3-oxo-3-(3-(5-(pyrazolo[1,5- Example 6ad 3 1.77 386 a]pyridin-3-yl)-3H-imidazo[4,5- b]pyridin-3-yl)piperidin-1- yl)propanenitrile (1) obtained as example 6, but using tert-butyl 3-aminopyrrolidine-1-carboxylate as starting material. (2) obtained as example 6, but using tert-butyl 4-(aminomethyl)piperidine-1-carboxylate as starting material.

Example 8 (S)-3-(9-(1-Acetylpiperidin-3yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of the compound obtained in example 6 (31 mg, 0.063 mmol) in anhydrous DMF (3 mL), acetic anhydride (0.007 mL, 0.08 mmol) and anhydrous TEA (0.02 mL, 0.127 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO₃ aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg₂SO₄, filtered and concentrated. The crude residue was flash chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 14.5 mg of the desired compound (57% yield).

LC-MS (method 2): t_(R)=1.8 min; m/z=403 (MH⁺).

Following a similar procedure to that described in example 8, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Compound name Starting material method (min) (MH⁺) 8a (S)-9-(1-acetylpiperidin-3-yl)-2- Example 6v 2 1.55 378 (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one 8b 3-(9-(1-acetylpiperidin-4-yl)-8-oxo- Example 6ab 1 13.31 403 8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 8c 9-(1-acetylpiperidin-4-yl)-2- Example 6d 4 1.30 378 (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one 8d (S)-3-(1-isobutyrylpiperidin-3-yl)-5- Example 6x 3 2.00 405 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one (1) 8e (S)-3-(9-(1-acetylpiperidin-3-yl)-7- Example 6c 3 1.88 417 methyl-8-oxo-8,9-dihydro-7H-purin- 2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 8f (S)-3-(1-acetylpiperidin-3-yl)-5- Example 6x 3 1.72 377 (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one 8g 3-(9-(1-acetylpiperidin-4-yl)-7- Example 6y 3 1.78 417 methyl-8-oxo-8,9-dihydro-7H-purin- 2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 8h 3-(9-(1-acetylazetidin-3-yl)-7- Example 6ac 3 1.62 389 methyl-8-oxo-8,9-dihydro-7H-purin- 2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile (1) using isobutyryl chloride instead of acetic anhydride as starting material.

Example 9 (S)-3-(9-(1-(Methylsulfonyl)piperidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of the compound obtained in example 6 (31 mg, 0.063 mmol) in anhydrous DMF (3 m L), methanesulphonic anhydride (13 mg, 0.08 mmol) and anhydrous TEA (0.02 mL, 0.127 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO₃ aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg₂SO₄, filtered and concentrated. The crude residue was chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 14.3 mg of the titled compound (52% yield).

LC-MS (method 1 PCB): t_(R)=2.08 min; m/z=439 (MH⁺).

Following a similar procedure to that described in example 9, but using the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Compound name Starting material method (min) (MH⁺) 9a (S)-9-(1-(methylsulfonyl)piperidin-3- Example 6v and 2 1.70 414 yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)- methanesulphonyl 7H-purin-8(9H)-one chloride 9b (S)-3-(8-oxo-9-(1- Example 6 and 5 2.48 467 (propylsulfonyl)piperidin-3-yl)-8,9- propane-1-sulfonyl dihydro-7H-purin-2-yl)pyrazolo[1,5- chloride a]pyridine-5-carbonitrile 9c (S)-3-(8-oxo-9-(1-(2,2,2- Example 6 and 2,2,2- 5 2.55 507 trifluoroethylsulfonyl)piperidin-3-yl)- trifluoroethanesulfonyl 8,9-dihydro-7H-purin-2- chloride yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9d (S)-3-(9-(1- Example 6 and 2- 3 2.70 481 (isobutylsulfonyl)piperidin-3-yl)-8- methylpropane-1- oxo-8,9-dihydro-7H-purin-2- sulfonyl chloride yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9e (S)-3-(8-oxo-9-(1-(3,3,3- Example 6 and 3,3,3- 3 2.70 521 trifluoropropylsulfonyl)piperidin-3- trifluoropropane-1- yl)-8,9-dihydro-7H-purin-2- sulfonyl chloride yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9f (S)-1-methyl-3-(1- Example 6g and 4 1.81 427 (methylsulfonyl)piperidin-3-yl)-5- methanesulphonyl (pyrazolo[1,5-a]pyridin-3-yl)-1H- chloride imidazo[4,5-b]pyridin-2(3H)-one 9g (S)-2-(5-methylpyrazolo[1,5- Example 6r and 3 1.87 428 a]pyridin-3-yl)-9-(1- methanesulphonyl (methylsulfonyl)piperidin-3-yl)-7H- chloride purin-8(9H)-one 9h 7-(2-oxopropyl)-9-(1-(2- Example 6d and 1- 4 1.66 448 oxopropyl)piperidin-4-yl)-2- chloropropan-2-one (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one 9i 9-(1-acetylpiperidin-4-yl)-7-methyl- Example 6t and 4 1.42 392 2-(pyrazolo[1,5-a]pyridin-3-yl)-7H- acetyl choride purin-8(9H)-one 9j (S)-3-(3-(1-isobutyrylpiperidin-3-yl)- Example 6e and 5 2.52 430 2-oxo-2,3-dihydro-1H-imidazo[4,5- isobutyryl chloride b]pyridin-5-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 9k (S)-3-(3-(1-(methylsulfonyl)piperidin- Example 6e and 3 1.92 438 3-yl)-2-oxo-2,3-dihydro-1H- methanesulphonyl imidazo[4,5-b]pyridin-5- chloride yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9l (S)-3-(7-methyl-9-(1- Example 6c and 3 2.05 453 (methylsulfonyl)piperidin-3-yl)-8- methanesulphonyl oxo-8,9-dihydro-7H-purin-2- chloride yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9m (S)-3-(9-(1-(ethylsulfonyl)piperidin- Example 6 and 3 1.90 453 3-yl)-8-oxo-8,9-dihydro-7H-purin-2- ethylsulphonyl yl)pyrazolo[1,5-a]pyridine-5- chloride carbonitrile 9n (S)-3-(9-(1-isobutyrylpiperidin-3-yl)- Example 6 and 3 1.95 431 8-oxo-8,9-dihydro-7H-purin-2- isobutyryl chloride yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9o 3-(7-methyl-9-(1- Example 6y and 3 1.95 453 (methylsulfonyl)piperidin-4-yl)-8- methanesulphonyl oxo-8,9-dihydro-7H-purin-2- chloride yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9p 3-(9-(1-(methylsulfonyl)piperidin-4- Example 6ab and 1 14.06 439 yl)-8-oxo-8,9-dihydro-7H-purin-2- methanesulphonyl yl)pyrazolo[1,5-a]pyridine-5- chloride carbonitrile 9q (S)-3-(1-(methylsulfonyl)piperidin-3- Example 6x and 3 1.85 413 yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)- methanesulphonyl 1H-imidazo[4,5-b]pyridin-2(3H)-one chloride 9r 3-(7-methyl-9-(1- Example 6ac and 3 2.30 425 (methylsulfonyl)azetidin-3-yl)-8-oxo- methanesulphonyl 8,9-dihydro-7H-purin-2- chloride yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9s (S)-3-(3-(1-acetylpiperidin-3-yl)-2- Example 6e and 5 2.25 402 oxo-2,3-dihydro-1H-imidazo[4,5- acetyl chloride b]pyridin-5-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 9t (S)-3-(1-(2-methoxyacetyl)piperidin- Example 6g and 2- 4 1.68 421 3-yl)-1-methyl-5-(pyrazolo[1,5- methoxyacetyl a]pyridin-3-yl)-1H-imidazo[4,5- chloride b]pyridin-2(3H)-one 9u (S)-1-methyl-5-(pyrazolo[1,5- Example 6g and 4 2.17 495 a]pyridin-3-yl)-3-(1-(2,2,2- 2,2,2- trifluoroethylsulfonyl)piperidin-3-yl)- trifluoroethanesulfonyl 1H-imidazo[4,5-b]pyridin-2(3H)-one chloride

Example 10 (S)-3-(9-(1-(2-Dimethylamino)acetyl)piperidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of N,N-dimethylglicine (10 mg, 0.095 mmol) in anhydrous DMF (2 mL), HOBt.H₂O was added. After 15 min, EDC.HCl (24 mg, 0.126 mmol) and the compound obtained in example 6 (31 mg, 0.063 mmol) were added. The reaction mixture was stirred at room temperature for 2.5 h and the solvent was concentrated off. It was quenched with saturated NaHCO₃ aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg₂SO₄, filtered and concentrated. The crude residue was chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 8.2 mg of the titled compound (29% yield).

LC-MS (method 3): t_(R)=1.67 min; m/z=446 (MH⁺).

Following a similar procedure to that described in example 10, but using the corresponding starting material, the following compound was obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 10a (S)-3-(9-(1-(2- Example 6 and 3 1.52 419 hydroxyacetyl)piperidin-3-yl)-8-oxo- glicolic acid 8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 10b (S)-3-(9-(1-(2-hydroxy-2- Example 6 and 2- 3 1.75 447 methylpropanoyl)piperidin-3-yl)-8- hydroxy-2- oxo-8,9-dihydro-7H-purin-2- methylpropanoic yl)pyrazolo[1,5-a]pyridine-5- acid carbonitrile 10c 3-(8-oxo-9-((S)-1-((S)- Example 6 and (S)- 3 1.75 459 tetrahydrofuran-2- tetrahydrofuran-2- carbonyl)piperidin-3-yl)-8,9-dihydro- carboxylic acid 7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 10d (S)-3-(9-(1-(2- Example 6 and 2- 3 1.65 433 methoxyacetyl)piperidin-3-yl)-8- methoxyacetic acid oxo-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 10e (S)-3-(9-(1-(2- Example 6 and 2- 3 2.20 459 ethylbutanoyl)piperidin-3-yl)-8-oxo- ethylbutanoic acid 8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 10f (S)-3-(9-(1-(2-(3-methylisoxazol-5- Example 6 and 2-(3- 3 1.82 484 yl)acetyl)piperidin-3-yl)-8-oxo-8,9- methylisoxazol-5- dihydro-7H-purin-2-yl)pyrazolo[1,5- yl)acetic acid a]pyridine-5-carbonitrile 10g 3-(9-((S)-1-((S)-2- Example 6 and (S)- 5 2.23 447 methoxypropanoyl)piperidin-3-yl)-8- 2-methoxypropanoic oxo-8,9-dihydro-7H-purin-2- acid yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 10h (S)-3-(8-oxo-9-(1-(3,3,3- Example 6 and 3 1.97 471 trifluoropropanoyl)piperidin-3-yl)- 3,3,3- 8,9-dihydro-7H-purin-2- trifluoropropanoic yl)pyrazolo[1,5-a]pyridine-5- acid carbonitrile 10i (S)-2-(5-methylpyrazolo[1,5- Example 6r and 3 1.85 406 a]pyridin-3-yl)-9-(1- propionic acid propionylpiperidin-3-yl)-7H-purin- 8(9H)-one 10j (S)-9-(1-(2-methoxyacetyl)piperidin- Example 6r and 2- 3 1.72 422 3-yl)-2-(5-methylpyrazolo[1,5- methoxyacetic acid a]pyridin-3-yl)-7H-purin-8(9H)-one 10k (S)-7-(2-methoxyacetyl)-9-(1-(2- Example 6r and 2- 3 2.13 494 methoxyacetyl)piperidin-3-yl)-2-(5- methoxyacetic acid methylpyrazolo[1,5-a]pyridin-3-yl)- 7H-purin-8(9H)-one 10l (S)-9-(1-acetylpiperidin-3-yl)-2-(5- Example 6r and 3 1.70 392 methylpyrazolo[1,5-a]pyridin-3-yl)- acetic acid 7H-purin-8(9H)-one 10m (S)-9-(1-(2-hydroxyacetyl)piperidin- Example 6r and 2- 3 1.60 408 3-yl)-2-(5-methylpyrazolo[1,5- hydroxyacetic acid a]pyridin-3-yl)-7H-purin-8(9H)-one 10n (S)-3-(9-(1- Example 6 and 3 1.88 429 (cyclopropanecarbonyl)piperidin-3- cyclopropanecarboxylic yl)-8-oxo-8,9-dihydro-7H-purin-2- acid yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 10o (S)-3-(1-(2-hydroxy-2- Example 6g and 2- 4 1.76 435 methylpropanoyl)piperidin-3-yl)-1- hydroxy-2- methyl-5-(pyrazolo[1,5-a]pyridin-3- methylpropanoic yl)-1H-imidazo[4,5-b]pyridin-2(3H)- acid one 10p (S)-3-(1-(2-hydroxyacetyl)piperidin- Example 6g and 2- 4 1.59 407 3-yl)-1-methyl-5-(pyrazolo[1,5- hydroxyacetic acid a]pyridin-3-yl)-1H-imidazo[4,5- b]pyridin-2(3H)-one 10q (S)-3-(1-(2- Example 6g and N,N- 4 1.65 434 (dimethylamino)acetyl)piperidin-3- dimethylglicine yl)-1-methyl-5-(pyrazolo[1,5- a]pyridin-3-yl)-1H-imidazo[4,5- b]pyridin-2(3H)-one 10r 1-methyl-5-(pyrazolo[1,5-a]pyridin- Example 6g and (S)- 4 1.76 447 3-yl)-3-((S)-1-((S)-tetrahydrofuran- tetrahydrofuran-2- 2-carbonyl)piperidin-3-yl)-1H- carboxylic acid imidazo[4,5-b]pyridin-2(3H)-one 10s (S)-1-methyl-5-(pyrazolo[1,5- Example 6g and 4 1.99 459 a]pyridin-3-yl)-3-(1-(3,3,3- 3,3,3- trifluoropropanoyl)piperidin-3-yl)- trifluoropropanoic 1H-imidazo[4,5-b]pyridin-2(3H)-one acid

Example 11 (S)-3-(2-(5-Cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N,N-dimethylpiperidine-1-sulfonamide

To a solution of the compound obtained in example 6 (110 mg, 0.22 mmol) in anhydrous DMF (3 mL), N,N-dimethylsulfamoyl chloride (0.03 mL, 0.27 mmol) and anhydrous TEA (0.13 mL, 0.90 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO₃ aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg₂SO₄, filtered and concentrated. The crude residue was chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 39.2 mg of the titled compound (38% yield).

LC-MS (method 1): t_(R)=1.95 min; m/z=468 (MH⁺).

Following a similar procedure to that described in example 11, but using the corresponding starting materials, the following compound was obtained:

Starting HPLC tR m/z Example Name Materials method (min) (MH+) 11a (S)-N,N-dimethyl-3- Example 4 2.05 456 (1-methyl-2-oxo-5- 6g (pyrazolo[1,5- a]pyridin-3-yl)- 1H-imidazo[4,5- b]pyridin-3(2H)- yl)piperidine-1- sulfonamide

Example 12 3-(9-(1-Acetylpyrrolidin-3-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile a) tert-Butyl 3-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate

Following a similar procedure to that described in example 1, but using tert-butyl 3-aminopyrrolidine-1-carboxylate instead of tetrahydro-2H-pyran-4-amine, the desired compound was obtained.

b) tert-Butyl 3-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)-7-methyl-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate

Following a similar procedure to that described in example 5, but using the compound obtained in previous section as starting material, the desired compound was obtained (25% yield).

c) 3-Methyl-8-oxo-9-(pyrrolidin-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile hydrochloride

Following a similar procedure to that described in example 6, but using the compound obtained in previous section as starting material, the desired compound was obtained (100% yield).

d) Title Compound

Following a similar procedure to that described in example 8, but using the compound obtained in previous section as starting material, the desired compound was obtained (22% yield).

LC-MS (method 2): t_(R)=1.67 min; m/z=403 (MH⁺).

Example 13 3-(7-Methyl-9-(1-methylsulfonyl)pyrrolidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Following a similar procedure to that described in example 9, but using the compound obtained in example 12 section c as starting material, the desired compound was obtained (15% yield),

LC-MS (method 2): t_(R)=1.83 min; m/z=439 (MH⁺).

Following a similar procedure to that described in example 13, but using the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 13a (S)-3-(7-methyl-9-(1- Example 6h 3 2.35 439 (methylsulfonyl)pyrrolidin-3-yl)-8- oxo-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 13b (R)-3-(7-methyl-9-(1- Example 6i 3 2.35 439 (methylsulfonyl)pyrrolidin-3-yl)-8- oxo-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 13c (S)-9-(1-(methylsulfonyl)pyrrolidin- Example 6j 3 1.53 400 3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)- 7H-purin-8(9H)-one 13d (S)-7-methyl-9-(1- Example 6k 3 1.77 414 (methylsulfonyl)pyrrolidin-3-yl)-2- (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one 13e (S)-3-(9-(1- Example 6l 3 1.63 425 (methylsulfonyl)pyrrolidin-3-yl)-8- oxo-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 13f (R)-1-methyl-3-(1- Example 6m 3 1.90 413 (methylsulfonyl)pyrrolidin-3-yl)-5- (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one 13g (R)-3-(1-(methylsulfonyl)pyrrolidin- Example 6n 3 1.72 399 3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)- 1H-imidazo[4,5-b]pyridin-2(3H)-one 13h (R)-3-(9-(1- Example 6o 3 1.62 425 (methylsulfonyl)pyrrolidin-3-yl)-8- oxo-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 13i (S)-3-(1-(methylsulfonyl)pyrrolidin- Example 6p 3 1.72 399 3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)- 1H-imidazo[4,5-b]pyridin-2(3H)-one 13j (S)-1-methyl-3-(1- Example 6q 3 1.92 413 (methylsulfonyl)pyrrolidin-3-yl)-5- (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one 13k (S)-7-methyl-9-(1- Example 6u 3 1.93 428 (methylsulfonyl)piperidin-3-yl)-2- (pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one

Example 14 (2R)-2-[2-(5-Cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]propanoic acid

To a suspension of example 1a (65 mg, 018 mmol) in dioxane (1.6 mL) and H₂O (0.8 mL) at 0° C., LiOH.H₂O (15 mg, 0.36 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h and room temperature for 26 h. The pH of the solution was adjusted to 5 by adding 10% HCl aqueous solution. The solvent was removed under vacuum and the resulting solid was suspended in Et₂O (10 mL) and concentrated. The resulting solid was washed with water (2×5 mL), hexanes (3 mL) and Et₂O (2×5 mL) to afford 57 mg of the desired product (91%).

LC-MS (method 1): t_(R)=13.59 min; m/z=350 (MH⁺).

Following a similar procedure to that described in example 14, but using the corresponding starting materials, the following compounds were obtained:

Starting HPLC t_(R) m/z Example Name Material method (min) (MH⁺) 14a (2S)-2-[2-(5- Example 1i 1 13.59 350 Cyanopyrazolo[1,5- a]pyridin-3-yl)-8- oxo-7,8-dihydro- 9H-purin-9- yl]propanoic acid 14b (S)-2-(8-oxo-2- Example 3e 3 1.10 325 (pyrazolo[1,5- a]pyridin-3-yl)- 7H-purin-9(8H)- yl)propanoic acid

Example 15 (2R)-2-[2-(5-Cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-N-(2,2,2-trifluoroethyl)propanamide

To a solution of HOBt.H₂O (31 mg, 0.20 mmol) and TEA (0.068 mL, 0.49 mmol) in THF (1 mL), example 14 (70 mg, 0.20 mmol) was added. After 15 min, EDC.HCl (40 mg, 0.21 mmol) and 2,2,2-trifluoroethylamine hydrochloride (14.6 mg, 0.11 mmol) were added and the resulting mixture was stirred at room temperature for 3.5 days. Then, it was quenched with H₂O (5 mL) and extracted with EtOAc (3×15 mL). The combined organic phases ware dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using MeOH/CH₂Cl₂ mixtures of increasing polarity as eluent, to afford 18 mg of the desired compound (50% yield).

LC-MS (method 1): t_(R)=15.34 min; m/z=431 (MH⁺).

Following a similar procedure to that described in example 15, but using the corresponding starting material, the following compound was obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 15a (2R)-(2-(5-cyanopyrazolo[1,5- Example 14 and N- 1 13.62 363 a]pyridin-3-yl)-8-oxo-7H-purin- methylamine 9(8H)-yl)-N-methylpropanamide 15b (2S)-2-[2-(5-cyanopyrazolo[1,5- (2S)-2-[2-(5- 3 2.08 459 a]pyridin-3-yl)-8-oxo-7,8-dihydro- cyanopyrazolo[1,5- 9H-purin-9-yl]-3-methyl-N-(2,2,2- a]pyridin-3-yl)-8-oxo- trifluoroethyl)butanamide 7,8-dihydro-9H-purin- 9-yl)-3-methylbutanoic acid (1) and 2,2,2- trifluoroethylamine 15c (R)-2-(2-(5-cyanopyrazolo[1,5- Example 14 and 2- 3 1.35 393 a]pyridin-3-yl)-8-oxo-7H-purin- aminoethanol 9(8H)-yl)-N-(2- hydroxyethyl)propanamide 15d (R)-2-(2-(5-cyanopyrazolo[1,5- Example 14 and 3 1.75 403 a]pyridin-3-yl)-8-oxo-7H-purin- cyclopropylmethanamine 9(8H)-yl)-N- (cyclopropylmethyl)propanamide 15e (R)-2-(2-(5-cyanopyrazolo[1,5- Example 14 and 3 1.48 420 a]pyridin-3-yl)-8-oxo-7H-purin- N1,N1- 9(8H)-yl)-N-(2- dimethylethane-1,2- (dimethylamino)ethyl)propanamide diamine 15f (R)-2-(2-(5-cyanopyrazolo[1,5- Example 14 and N- 3 1.57 377 a]pyridin-3-yl)-8-oxo-7H-purin- ethylamine 9(8H)-yl)-N-ethylpropanamide 15g (R)-2-(2-(5-cyanopyrazolo[1,5- Example 14 and N- 3 1.70 391 a]pyridin-3-yl)-8-oxo-7H-purin- isopropylamine 9(8H)-yl)-N-isopropylpropanamide 15h (R)-2-(2-(5-cyanopyrazolo[1,5- Example 14 and N,N- 3 1.53 377 a]pyridin-3-yl)-8-oxo-7H-purin- dimethylamine 9(8H)-yl)-N,N-dimethylpropanamide 15i (S)-2-(2-(5-cyanopyrazolo[1,5- Example 14a and 3 1.72 431 a]pyridin-3-yl)-8-oxo-7H-purin- 2,2,2- 9(8H)-yl)-N-(2,2,2- trifluoroethylamine trifluoroethyl)propanamide 15j (S)-N-methyl-2-(8-oxo-2- Example 14b and N- 3 1.35 338 (pyrazolo[1,5-a]pyridin-3-yl)-7H- methylamine purin-9(8H)-yl)propanamide 15k (S)-N,N-dimethyl-2-(8-oxo-2- Example 14b and N,N- 5 1.90 352 (pyrazolo[1,5-a]pyridin-3-yl)-7H- dimethylamine purin-9(8H)-yl)propanamide (1) Obtained as example 14 but using HCl/Dioxane 4M/H₂O (1:1) instead of LiOH•H2O, and L-Valine methyl ester hydrochloride as starting material.

Example 16 3-(7-(2-Methoxyethyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of example 1 (50 mg, 0.14 mmol) in DMF (8 mL), 55-65% NaH dispersion in mineral oil (6 mg, 0.15 mmol) was added and the resulting solution was stirred at room temperature for 10 min. Then 2-bromoethyl methyl ether (0.032 mL, 0.34 mmol) was added and the reaction mixture was stirred at 50° C. for 14.5 h. The reaction mixture was quenched with H₂O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using EtOAc/hexanes mixtures of increasing polarity as eluent, to afford 36 mg of the desired compound (62% yield).

LC-MS (method 1): t_(R)=16.17 min; m/z=420 (MH⁺).

Following a similar procedure to that described in example 16, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 16a (S)-3-(9-(1-(2- 2-bromo-N,N- 2 1.95 499 cyanoacetyl)piperidin-3-yl)-7-(2- dimethylethanamine (dimethylamino)ethyl)-8-oxo-8,9- and example 1b (1) dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 16b (S)-3-(7-(2-(dimethylamino)ethyl)-8- 2-bromo-N,N- 2 1.83 432 oxo-9-(piperidin-3-yl)-8,9-dihydro- dimethylethanamine 7H-purin-2-yl)pyrazolo[1,5- and example 1b (2) a]pyridine-5-carbonitrile 16c 7-(2-(dimethylamino)ethyl)-2- 2-bromo-N,N- 2 1.921 408 (pyrazolo[1,5-a]pyridin-3-yl)-9- dimethylethanamine (tetrahydro-2H-pyran-4-yl)-7H- and example 3 purin-8(9H)-one) 16d 3-(7-(2-(dimethylamino)ethyl)-8- 2-bromo-N,N- 1 14.79 433 oxo-9-(tetrahydro-2H-pyran-4-yl)- dimethylethanamine 8,9-dihydro-7H-purin-2- and example 1 yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 16e 3-(7-(2-(dimethylamino)ethyl)-9-(8- 2-bromo-N,N- 4 2.12 499 fluorochroman-4-yl)-8-oxo-8,9- dimethylethanamine dihydro-7H-purin-2-yl)pyrazolo[1,5- and example 1p a]pyridine-5-carbonitrile 16f 3-(9-(8-fluorochroman-4-yl)-7-(2- 2-bromoethyl methyl 4 2.20 486 methoxyethyl)-8-oxo-8,9-dihydro- ether and example 7H-purin-2-yl)pyrazolo[1,5- 1p a]pyridine-5-carbonitrile 16g 3-(9-(8-fluorochroman-4-yl)-7-(3- 3-bromopropan-1-ol 4 1.96 486 hydroxypropyl)-8-oxo-8,9-dihydro- and example 1p 7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 16h (S)-3-(3-(1-(2- 2-bromo-N,N- 4 1.73 473 (dimethylamino)ethyl)-2-oxo-5- dimethylethanamine (pyrazolo[1,5-a]pyridin-3-yl)-1H- and example 2a (1) imidazo[4,5-b]pyridin-3(2H)- yl)piperidin-1-yl)-3- oxopropanenitrile 16i (S)-3-(3-(1-(2-methoxyethyl)-2-oxo- 2-bromoethyl methyl 4 1.82 460 5-(pyrazolo[1,5-a]pyridin-3-yl)-1H- ether and example imidazo[4,5-b]pyridin-3(2H)- 2a (1) yl)piperidin-1-yl)-3- oxopropanenitrile 16j (S)-3-(3-(1-(cyclopropylmethyl)-2- (bromomethyl)cyclo 4 2.08 456 oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)- propane and 1H-imidazo[4,5-b]pyridin-3(2H)- example 2a (1) yl)piperidin-1-yl)-3- oxopropanenitrile (1) followed by a similar procedure to that described in example 6 (tert-butoxtcarbonyl cleavage) and 7 (amide formation). (2) followed by tert-butoxycarbonyl cleavage as example 6

Example 17 3(7-(2-Hydroxyethyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile a) 3-(7-(2-tert-Butyldimethylsilyloxy)ethyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of example 1 (50 mg, 0.14 mmol) in DMF (8 mL), 55-65% NaH dispersion in mineral oil (6 mg, 0.15 mmol) was added. The resulting solution was stirred at room temperature for 10 min. Then (2-bromoethoxy)-tert-butyldimethylsilane (0.074 mL, 0.34 mmol) was added and the reaction was stirred at 50° C. for 14.5 h. The reaction mixture was quenched with H₂O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using hexanes/EtOAc mixtures of increasing polarity as eluent, to afford 55 mg of the desired compound (76% yield).

b) Title Compound

To a solution of the compound obtained in the previous section (55 mg, 0.10 mmol) in THF (5 mL) 1 M TBAF solution in THF (0.14 mL, 0.14 mmol) was added and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was quenched with H₂O (10 mL) and extracted with EtOAc (3×10 mL) and CH₂Cl₂ (2×10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 39 mg of the desired compound (91% yield).

LC-MS (method 1): t_(R)=14.13 min; m/z=406 (MH⁺).

Following a similar procedure to that described in example 17, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 17a (S)-3-(9-(1-(2- Example 1b (1) 1 1.68 472 cyanoacetyl)piperidin-3-yl)-7-(2- hydroxyethyl)-8-oxo-8,9-dihydro- 7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 17b (S)-3-(7-(2-hydroxyethyl)-8-oxo-9- Example 1b (2) 1 1.55 405 (piperidin-3-yl)-8,9-dihydro-7H- purin-2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 17c 3-(9-(8-fluorochroman-4-yl)-7-(2- Example 1p 1 15.99 472 hydroxyethyl)-8-oxo-8,9-dihydro- 7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile (1) Followed by a similar procedure to that described in example 6 (tert-butoxtcarbonyl cleavage) and 7 (amide formation). (2) Followed by tert-butoxycarbonyl cleavage as example 6

Example 18 3-(9-Tetrahydro-2H-pyran-4-yl-9H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a suspension of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in EtOH (1 mL), PTSA monohydrate (5.7 mg, 0.03 mmol) and triethylorthoformate (1 mL) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 123° C. and 270 W for 30 min. Then, it was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 81 mg of the desired compound (79% yield).

LC-MS (method 1): t_(R)=14.56 min; m/z=346 (MH⁺).

Following a similar procedure to that described in example 18, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 18a 3-(8-methyl-9-tetrahydro-2H-pyran- Example 1 section d 1 14.77 360 4-yl-9H-purin-2-yl)pyrazolo[1,5- and a]pyridine-5-carbonitrile triethylorthoacetate 18b 3-(9-(4,4-difluorocyclohexyl)-8- triethylorthoacetate 2 2.17 394 methyl-9H-purin-2-yl)pyrazolo[1,5- and 3-(5-amino-4-(4,4- a]pyridine-5-carbonitrile difluorocyclohexylamino)- pyrimidin-2- yl)pyrazolo[1,5- a]pyridine-5- carbonitrile (1) 18c 3-(9-(1,1-dioxotetrahydrothien-3-yl)- triethylorthoacetate 2 1.65 394 8-methyl-9H-purin-2- and 3-(5-amino-4-(1,1- yl)pyrazolo[1,5-a]pyridine-5- dioxotetrahydrothien- carbonitrile 3-yl)aminopyrimidin-2- yl)pyrazolo[1,5- a]pyridine-5- carbonitrile (2) 18d 5-(pyrazolo[1,5-a]pyridin-3-yl)-3- Reference example 2g 3 1.85 320 (tetrahydro-2H-pyran-4-yl)-3H- and imidazo[4,5-b]pyridine triethylorthoformate 18e (S)-tert-butyl 3-(5-(5- Reference example 2h 3 2.33 444 cyanopyrazolo[1,5-a]pyridin-3-yl)- and 3H-imidazo[4,5-b]pyridin-3- triethylorthoformate yl)piperidine-1-carboxylate 18f (S)-tert-butyl 3-(5-(5- Reference example 2h 3 2.57 458 cyanopyrazolo[1,5-a]pyridin-3-yl)-2- and methyl-3H-imidazo[4,5-b]pyridin-3- triethylorthoacetate yl)piperidine-1-carboxylate 18g 2-methyl-5-(pyrazolo[1,5-a]pyridin- Reference example 2g 3 1.92 334 3-yl)-3-(tetrahydro-2H-pyran-4-yl)- and 3H-imidazo[4,5-b]pyridine triethylorthoacetate 18h 3-(9-(trans-4-hydroxycyclohexyl)-8- Reference example 2j 3 1.70 374 methyl-9H-purin-2-yl)pyrazolo[1,5- and a]pyridine-5-carbonitrile triethylorthoacetate 18i (S)-tert-butyl 3-(5-(pyrazolo[1,5- Reference example 2d 3 1.77 386 a]pyridin-3-yl)-3H-imidazo[4,5- and b]pyridin-3-yl)piperidine-1- triethylorthoformate carboxylate (1) obtained in example 1e section d (2) obtained in example 1f section d

Example 19 3-(3-(Tetrahydro-2H-pyran-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a suspension of the compound obtained in example 2 section d (33.6 mg, 0.1 mmol) in EtOH (1.5 mL), citric acid (2 mg, 0.1 mmol) and triethyl orthoformate (340 μL, 2 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 145° C. and 270 W for 2.5 hours. The crude residue was cromategraphed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 14.2 mg of the desired product (41% yield).

LC-MS (method 3): t_(R)=1.76 min; m/z=345 (MH⁺).

Following a similar procedure to that described in example 19, but using the corresponding starting material, the following compound was obtained:

Starting HPLC t_(R) m/z Example Name Material method (min) (MH⁺) 19a (S)-3-(3-(1- Reference 5 2.22 386 acetylpiperidin-3- example 2f yl)-3H-imidazo- [4,5-b]pyridin- 5-yl)pyrazolo- [1,5-a]pyridine- 5-carbonitrile

Example 20 3-(2-Methyl-3-(tetrahydro-2H-pyran-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of the compound obtained in example 2 section d (56.4 mg, 0.169 mmol) in EtOH (1.5 mL), PTSA monohydrate (3.21 mg, 0.017 mmol) and triethyl orthoacetate (547 mg, 3.37 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 145° C. and 270 W for 2.5 hours. The crude residue was cromategraphed on a silica gel flash system (ISCO Rf) using CH₂Cl₂/MeOH mixtures of increasing polarity, a eluent to afford the desired product (15% yield).

LC-MS (method 3): t_(R)=1.79 min; m/z=359.5 (MH⁺).

Example 21 3-(8-(1-Methyl-1H-imidazol-2-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in AcOH (0.025 mL) and DMA (2.5 mL), 1-methyl-1H-imidazole-2-carbaldehyde (46 mg, 0.42 mmol) was added. The reaction mixture was stirred in a sealed tube at 140° C. for 19 h. The crude mixture was quenched with H₂O (10 mL), extracted with EtOAc (3×10 mL) and the combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using hexanes/EtOAc mixtures of increasing polarity as eluent, to afford 40 mg of the desired compound (31% yield).

LC-MS (method 1): t_(R)=16.436 min; m/z=426 (MH⁺).

Following a similar procedure to that described in example 21, but using the corresponding starting material, the following compound was obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 21a 3-(8-(pyrimidin-5-yl)-9-(tetrahydro- Example 1 section d 4 1.67 424 2H-pyran-4-yl)-9H-purin-2- and pyrimidine-5- yl)pyrazolo[1,5-a]pyridine-5- carbaldehyde carbonitrile 21b 3-(9-(8-fluorochroman-4-yl)-8- Reference example 1 16.34 490 (pyrimidin-5-yl)-9H-purin-2- 2e and pyrimidine-5- yl)pyrazolo[1,5-a]pyridine-5- carbaldehyde carbonitrile 21c 3-(9-(8-fluorochroman-4-yl)-8-(1- Reference example 1 18.4 492 methyl-1H-imidazol-2-yl)-9H-purin- 2e and 1-methyl-1H- 2-yl)pyrazolo[1,5-a]pyridine-5- imidazole-2- carbonitrile carbaldehyde 21d 2-(pyrazolo[1,5-a]pyridin-3-yl)-8- Reference example 3 2.15 386 (1H-pyrrol-2-yl)-9-(tetrahydro-2H- 2c and 1H-pyrrole-2- pyran-4-yl)-9H-purine carbaldehyde 21e 8-(5-methylthiophen-2-yl)-2- Reference example 3 2.52 417 (pyrazolo[1,5-a]pyridin-3-yl)-9- 2c and 5- (tetrahydro-2H-pyran-4-yl)-9H- methylthiophene-2- purine carbaldehyde 21f 8-(1-methyl-1H-imidazol-2-yl)-2- Reference example 3 2.05 401 (pyrazolo[1,5-a]pyridin-3-yl)-9- 2c and 1-methyl-1H- (tetrahydro-2H-pyran-4-yl)-9H- imidazole-2- purine carbaldehyde 21g 2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Reference example 3 2.22 403 (tetrahydro-2H-pyran-4-yl)-8-(2,2,2- 2c and 3,3,3- trifluoroethyl)-9H-purine trifluoropropanal 21h 8-(1H-pyrazol-3-yl)-2-(pyrazolo[1,5- Reference example 3 1.83 387 a]pyridin-3-yl)-9-(tetrahydro-2H- 2c and 1H-pyrazole- pyran-4-yl)-9H-purine 3-carbaldehyde 21i 8-(1-methyl-1H-pyrrol-2-yl)-2- Reference example 3 2.33 400 (pyrazolo[1,5-a]pyridin-3-yl)-9- 2c and 1-methyl-1H- (tetrahydro-2H-pyran-4-yl)-9H- pyrrole-2- purine carbaldehyde 21j 2-(2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Reference example 3 2.43 404 (tetrahydro-2H-pyran-4-yl)-9H- 2c and thiazole-2- purin-8-yl)thiazole carbaldehyde 21k 2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Reference example 3 2.32 403 (tetrahydro-2H-pyran-4-yl)-8- 2c and thiophene-2- (thiophen-2-yl)-9H-purine carbaldehyde 21l (S)-3-(9-(1-acetylpiperidin-3-yl)-8- Reference example 3 1.8 465 (pyrimidin-5-yl)-9H-purin-2- 2 and pyrimidine-5- yl)pyrazolo[1,5-a]pyridine-5- carbaldehyde carbonitrile 21m (S)-tert-butyl 3-(2-methyl-5- Reference example 3 2.60 433 (pyrazolo[1,5-a]pyridin-3-yl)-3H- 2d and imidazo[4,5-b]pyridin-3- acetaldehydee yl)piperidine-1-carboxylate

Example 22 3-[8-(Ethylamino)-9-tetrahydro-2H-pyran-4-yl-9H-purin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile

To a suspension of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in CH₂C₂ (2 mL), ethyl isothiocyanate (0.042 mL, 0.48 mmol), EDC.HCl (171 mg, 0.89 mmol) and DIPEA (0.25 mL, 1.49 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 80° C. and 150 W for 30 min. Then, it was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 42 mg of the desired compound (36% yield).

LC-MS (method 1): t_(R)=15.64 min; m/z=389 (MH⁺).

Following a similar procedure to that described in example 22, but using the corresponding starting material, the following compound was obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 22a 3-(8-(pyridin-3-ylamino)-9- Example 1 section 1 16.20 438 (tetrahydro-2H-pyran-4-yl)-9H- d, pyridine-3- purin-2-yl)pyrazolo[1,5-a]pyridine-5- isothiocyanate carbonitrile 22b 3-(8-(ethylamino)-9-(8- Reference example 1 17.07 455 fluorochroman-4-yl)-9H-purin-2- 2e and ethyl yl)pyrazolo[1,5-a]pyridine-5- isothiocyanate carbonitrile 22c 3-(9-(8-fluorochroman-4-yl)-8- Reference example 1 17.22 504 (pyridin-3-ylamino)-9H-purin-2- 2e and pyridine-3- yl)pyrazolo[1,5-a]pyridine-5- isothiocyanate carbonitrile

Example 23 8-Cyclopentyl-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purine

To a solution of reference example 2c (0.05 g, 0.16 mmol) in DMF (1 mL), cyclopentanecarbaldehyde (0.018 mL, 0.17 mmol) and sodium bisulfite (0.030 g, 0.29 mmol) were added. The reaction mixture was stirred at 130° C. for 6 h. The solvent was concentrated off and the crude residue was cromatographed on a silica gel flash system (ISCO Companion) using CH₂Cl₂/MeOH mixtures of increasing polarity as eluent to afford 37 mg of the desired product (60% yield).

LC-MS (method 3): t_(R)=2.40 min; m/z=339 (MH⁺).

Following a similar procedure to that described in example 23, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 23a (S)-3-(9-(1-acetylpiperidin-3-yl)-8- Reference example 2 5 2.42 415 ethyl-9H-purin-2-yl)pyrazolo[1,5- and propionaldehyde a]pyridine-5-carbonitrile 23b (S)-3-(9-(1-acetylpiperidin-3-yl)-8- Reference example 2 5 2.57 429 isopropyl-9H-purin-2- and isobutyraldehyde yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 23c (S)-3-(9-(1-acetylpiperidin-3-yl)-8- Reference example 2 3 1.78 401 methyl-9H-purin-2-yl)pyrazolo[1,5- and acetaldehyde a]pyridine-5-carbonitrile 23d 8-cyclopropyl-2-(pyrazolo[1,5- Reference example 2c 3 2.05 361 a]pyridin-3-yl)-9-(tetrahydro-2H- and pyran-4-yl)-9H-purine cyclopropanecarbaldehyde

Example 24 (S)-3-(1-Acetylpiperidin-3-yl)-1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

To a solution of example 6g (250 mg, 0.65 mmol) in pyridine (10 mL), acetyl chloride (0.92 mL, 1.3 mmol) was added. The reaction mixture was stirred at room temperature for 5 h. The solvent was concentrated off and the crude residue was cromatographed on a silica gel flash system (SP1 Biotage) using EtOAc/MeOH mixtures of increasing polarity as eluent to afford 196 mg of the desired product (78% yield).

LC-MS (method 4): t_(R)=1.66 min; m/z=391 (MH⁺).

Following a similar procedure to that described in example 24, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 24a (S)-1-methyl-3-(1-pivaloylpiperidin- Example 6g and 4 2.10 433 3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)- pivaloyl chloride 1H-imidazo[4,5-b]pyridin-2(3H)-one 24b (S)-3-(1-(4-fluorobenzoyl)piperidin- Example 6g and 4- 4 2.11 472 3-yl)-1-methyl-5-(pyrazolo[1,5- fluorobenzoyl chloride a]pyridin-3-yl)-1H-imidazo[4,5- b]pyridin-2(3H)-one 24c (S)-1-methyl-3-(1- Example 6g and 4 1.79 405 propionylpiperidin-3-yl)-5- propionyl chloride (pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one

Example 25 (S)-1-(3-(1-Methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile

To a solution of 1-cyano-1-cyclopropanecarboxylic acid (65 mg. 0.58 mmol), in DMF (7 mL), DIEA (0.31 mL, 1.7 mmol), example 6g (248 mg, 0.64 mmol) and HBTU (266 mg, 0.70 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was concentrated off and the crude residue was cromatographed on a silica gel flash system (SP1 Storage) using EtOAc/MeOH mixtures of increasing polarity as eluent to afford the desired with quantitative yield.

LC-MS (method 4): t_(R)=1.92 min; m/z=442 (MH⁺).

Following a similar procedure to that described in example 25, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Name Starting Materials method (min) (MH⁺) 25a 9-(1-isobutyrylpiperidin-4-yl)-2- Example 6d and 4 1.59 406 (pyrazolo[1,5-a]pyridin-3-yl)-7H- isobutyric acid purin-8(9H)-one 25b 9-(1-(2- Example 6d and 2- 4 1.34 421 (dimethylamino)acetyl)piperidin-4- (dimethylamino)acetic yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)- acid 7H-purin-8(9H)-one

Example 26 (S)-Methyl 3-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)piperidine-1-carboxylate

To a solution of example 6 (200 mg, 0.26 mmol) in DMF (2.6 mL), methyl chloroformate (27 mg, 0.28 mmol) and DIPEA (0.068 mL, 0.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, dissolved in CH₂Cl₂, and washed thrice with saturated NaHCO₃ aqueous solution. The combined organic phases were dried over MgSO₄ and concentrated to dryness. The crude residue was cromatographed on a silica gel flash system (ISCO Combiflash) using CH₂Cl₂/MeOH mixtures of increasing polarity as eluent to afford 36 mg of the desired product (32% yield).

LC-MS (method 5): t_(R)=2.37 min; m/z=419 (MH⁺).

Following a similar procedure to that described in example 26, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Name Starting Materials method (min) (MH⁺) 26a (S)-ethyl 3-(2-(5-cyanopyrazolo[1,5- Example 6 and ethyl 5 2.53 433 a]pyridin-3-yl)-8-oxo-7H-purin- chloroformate 9(8H)-yl)piperidine-1-carboxylate 26b (S)-isobutyl 3-(2-(5- Example 6 and 5 2.82 461 cyanopyrazolo[1,5-a]pyridin-3-yl)-8- isobutyl chloroformate oxo-7H-purin-9(8H)-yl)piperidine-1- carboxylate 26c (S)-3-(2-(5-cyanopyrazolo[1,5- Example 6 and 5 2.33 446 a]pyridin-3-yl)-8-oxo-7H-purin- isopropyl isocyanate 9(8H)-yl)-N-isopropylpiperidine-1- carboxamide 26d (S)-N-tert-butyl-3-(2-(5- Example 6 and tert- 5 2.52  460° cyanopyrazolo[1,5-a]pyridin-3-yl)-8- butyl isocyanate oxo-7H-purin-9(8H)-yl)piperidine-1- carboxamide 26e (S)-ethyl 9-(1-(2- Example 7f and ethyl 5 2.62 475 cyanoacetyl)piperidin-3-yl)-8-oxo-2- chloroformate (pyrazolo[1,5-a]pyridin-3-yl)-8,9- dihydro-7H-purine-7-carboxylate 26f (S)-3-(3-(7-acetyl-8-oxo-2- Example 7f and acetyl 5 2.60 445 (pyrazolo[1,5-a]pyridin-3-yl)-7H- chloride purin-9(8H)-yl)piperidin-1-yl)-3- oxopropanenitrile 26g (S)-9-(1-acetylpiperidin-3-yl)-7- Example 6u and acetyl 3 1.80 392 methyl-2-(pyrazolo[1,5-a]pyridin-3- chloride yl)-7H-purin-8(9H)-one 26h (S)-N-isopropyl-3-(1-methyl-2-oxo- Example 7p and 4 1.85 434 5-(pyrazolo[1,5-a]pyridin-3-yl)-1H- isopropyl isocyanate imidazo[4,5-b]pyridin-3(2H)- yl)piperidine-1-carboxamide 26i (S)-3-(3-(1-acetyl-2-oxo-5- Example 7p and acetyl 4 2.01 444 (pyrazolo[1,5-a]pyridin-3-yl)-1H- chloride imidazo[4,5-b]pyridin-3(2H)- yl)piperidin-1-yl)-3- oxopropanenitrile 26j (S)-ethyl 3-(1-(2- Example 7p and ethyl 4 1.97 474 cyanoacetyl)piperidin-3-yl)-2-oxo-5- chloroformate (pyrazolo[1,5-a]pyridin-3-yl)-2,3- dihydro-1H-imidazo[4,5-b]pyridine- 1-carboxylate

Example 27 (S)-3-(9-(1-(1-Cyanocyclopropanecarbonyl)piperidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Following a similar procedure to that described in example 25, but using HATU instead of HBTU, and example 6 instead of example 6g, the desired compound was obtained (30% yield).

LC-MS (method 3): t_(R)=1.87 min; m/z=454 (MH⁺).

Following a similar procedure to that described in example 27, but using the corresponding starting materials, the following compound was obtained:

Exam- Starting HPLC tR m/z ple Name Materials method (min) (MH+) 27a (S)-3-(9-(1-(1-hydroxy- Example 3 1.7 455 cyclopropanecarbonyl)- 6 and 1- piperidin-3-yl)-8-oxo- hydroxy- 8,9-dihydro-7H-purin- cyclo- 2-yl)pyrazolo- propane- [1,5-a]pyridine- carboxylic 5-carbonitrile acid

Example 28

(R)-3-(9-(1-Hydroxypropan-2-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of example 14 (60 mg, 0.17 mmol) in THF (10 mL) at 0° C., 1 M THF borane complex solution in THF (0.69 mL, 0.69 mmol) was added. The reaction mixture was stirred at room temperature overnight, quenched with MeOH (10 mL) and the reaction mixture was evaporated under reduced pressure. The crude residue was cromatographed on a silica gel flash system (ISCO Combiflash) using CH₂Cl₂/MeOH mixtures of increasing polarity as eluent to afford 4 mg of the desired product (7% yield).

LC-MS (method 3): t_(R)=2.02 min; m/z=336 (MH⁺).

Example 29 (S)-3-(3-(2-(5-Methylpyrazolo[1,5-a]pyridin-3-yl)-9H-purin-9-yl)piperidin-1-yl)-3-oxopropanenitrile a) (S)-tert-Butyl 3-(2-(5-methylpyrazolo[1,5-a]pyridin-3yl)-9H-purin-9-yl)piperidine-1-carboxylate

Following a similar procedure to that described in example 18, but using reference example 2a instead of the compound obtained in example 1 section d, the desired compound was obtained (10% yield).

LC-MS (method 3): t_(R)=2.53 min; m/z=434 (MH⁺).

b) (S)-2-(5-Methylpyrazolo[1,5-a]pyridin-3-yl)-9-(piperidin-3-yl)-9H-purine hydrochloride

Following a similar procedure to that described in example 6, but using the compound obtained in the previous section, the desired compound was obtained (quantitative yield).

LC-MS (method 3): t_(R)=1.7 min; m/z=334 (MH⁺).

c) Title Compound

Following a similar procedure to that described in example 7, but using the compound obtained in the previous section, the desired compound was obtained (57% yield).

LC-MS (method 3): t_(R)=1.78 min; m/z=401 (MH⁺).

Example 30 1-(4-(2-Pyrazolo[1,5-a]pyridin-3-yl)-9H-purin-9yl)piperidin-1-yl)ethanone a) 9-(Piperidin-4-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9H-purine hydrochloride

Following a similar procedure to that described in example 29 section a and b, but using the compound obtained in reference example 2b instead of reference example 2a, the desired compound was obtained (10% yield).

b) Title Compound

Following a similar procedure to that described in example 24, but using the compound obtained in the previous section, the desired compound was obtained (quantitative yield).

LC-MS (method 4): t_(R)=1.35 min; m/z=362 (MH⁺).

Example 31 (S)-(9-(1-(2-Cyanoacetyl)piperidin-3-yl)-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-8,9-dihydro-7H-purin-7-yl)methyl acetate a) (S)-tert-Butyl 3-(7-(acetoxymethyl)-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1-carboxylate

Following a similar procedure to that described in example 4, but using the compound obtained in example 3b instead of example 1 and bromomethyl acetate instead of methyl iodide, the desired compound was obtained (83% yield).

LC-MS (method 3): t_(R)=2.72 min; m/z=508 (MH⁺).

b) (S)-(8-Oxo-9-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-8,9-dihydro-7H-purin-7-yl)methyl acetate hydrochloride

Following a similar procedure to that described in example 6, but using the compound obtained in the previous section, the desired compound was obtained (quantitative yield).

LC-MS (method 3): t_(R)=1.80 min; m/z=408 (MH⁺).

c) Title Compound

Following a similar procedure to that described in example 7, but using the compound obtained in the previous section, the desired compound was obtained (36% yield).

LC-MS (method 3): t_(R)=1.82 min; m/z=475 (MH⁺).

Following a similar procedure to that described in example 31, but using the corresponding starting materials, the following compound was obtained:

Exam- Starting HPLC tR m/z ple Name Materials method (min) (MH+) 31a (S)-(3-(1-(2- Example 4 1.84 474 cyanoacetyl)- 7p piperidin-3-yl)-2-oxo- 5-(pyrazolo[1,5-a]- pyridin-3-yl)-2,3- dihydro-1H- imidazo[4,5-b]pyridin- 1-yl)methyl acetate

Example 32 (R)-3-(9-(1-Hydroxypropan-2-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of example 28 (20 mg, 0.06 mmol) in AcN (2 mL) and DMF (0.5 mL) silver (I) oxide (23 mg, 0.12 mmol) and methyl iodide (0.005 mL, 0.09 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a plug of Celite® and the solvent was evaporated under reduced pressure. The crude residue was cromatographed on a silica gel flash system (ISCO Combiflash) using CH₂Cl₂/MeOH mixtures of increasing polarity as eluent to afford 6 mg of the desired product (29% yield).

LC-MS (method 3): t_(R)=1.75 min; m/z=350 (MH⁺).

Example 33 2-(Pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-8-amine

To a solution of reference example 2c (144 mg, 0.46 mmol) in EtOH (4 mL), cyanogen bromide (147 mg, 1.39 mmol) was added. The reaction mixture was stirred at 70° C. overnight. The reaction mixture was evaporated under reduced pressure dissolved in EtOAc, and washed thrice with saturated NaHCO₃ aqueous solution. The combined organic phases were dried over MgSO₄ and concentrated to dryness. The reaction crude was used in next step without further purification.

LC-MS (Method 3): t_(R)=1.53 min; m/z=335 (MH⁺)

Example 34 1-(2-(Pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-8-yl)pyrrolidin-2-one

To a suspension of example 33 (25 mg, 0.075 mmol) in DMF (1.5 mL), DIPEA (0.04 mL, 0.22 mmol) and 4-bromobutyryl chloride (0.01 mL, 0.082 mmol) ware added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and 1.7 mg of the title compound were obtained (yield 6%) after HPLC preparative purification.

LC-MS (method 3): t_(R)=1.82 min; m/z=404 (MH⁺)

Following a similar procedure to that described in example 34, but using in each case the corresponding starting materials, the following compounds were obtained:

HPLC t_(R) m/z Example Name Starting Materials method (min) (MH⁺) 34a N-(2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Example 33 and 3 1.97 406 (tetrahydro-2H-pyran-4-yl)-9H- isobutyryl chloride purin-8-yl)isobutyramide 34b N-(2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Example 33 and 3 1.77 392 (tetrahydro-2H-pyran-4-yl)-9H- propionyl chloride purin-8-yl)propionamide 34c N-(2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Example 33 and acetyl 3 1.60 378 (tetrahydro-2H-pyran-4-yl)-9H- chloride purin-8-yl)acetamide

Example 35 3-(9-(trans-4-Hydroxycyclohexyl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile a) 3-(9-(trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a suspension of example 1a (584 mg, 1.55 mmol) in DMF (15 mL), imidazole (265 mg, 3.89 mmol) and tert-butylchlorodimethylsilane (281 mg, 1.86 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness, dissolved in CH₂Cl₂ and washed thrice with water. The combined organic phases were dried over MgSO₄ and concentrated to dryness. The reaction crude was used in next step without further purification

LC-MS (method 3): t_(R)=3.38 min; m/z=490 (MH⁺)

b) 3-(9-(trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Following a similar procedure to that described in example 5, but using the compound obtained in the previous section, the desired compound was obtained (72% yield).

LC-MS (method 2): t_(R)=3.67 min; m/z=504 (MH⁺).

c) Title Compound

To a suspension of the compound obtained in the previous section (246 mg, 0.488 mmol) in AcN (10 mL), at 0° C., 1 M TBAF solution in THF (0.73 mL, 0.73 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness, dissolved in EtOAc and washed thrice with water. The combined organic phases were dried over MgSO4 and concentrated to dryness. The crude residue was cromatographed on a silica gel flash system (ISCO Combiflash) using CH₂Cl₂/MeOH mixtures of increasing polarity as eluent to afford 77 mg of the desired product (40% yield).

LC-MS (method 3): t_(R)=1.82 min; m/z=390 (MH⁺).

Example 36 2-(2-(5-Cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-(2,2,2-trifluoroethyl)acetamide a) 2-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)acetic acid

Following a similar procedure to that described in example 14, but using the compound obtained in example 1n instead of example 1a the desired compound was obtained

LC-MS (method 3): t_(R)=1.05 min; m/z=336 (MH⁺).

b) Title Compound

Following a similar procedure to that described in example 15, but using the compound obtained in the previous section and 2,2,2-trifluoroethylamine, the desired compound was obtained.

LC-MS (method 3): t_(R)=1.065 min; m/z=417 (MH⁺).

Following a similar procedure to that described in example 36, but using the corresponding starting materials, the following compound was obtained:

Starting HPLC tR m/z Example Name Materials method (min) (MH+) 36a 2-(2-(5- N- 3 1.40 363 cyanopyrazolo- ethylamine [1,5-a]pyridin-3- yl)-8-oxo-7H-purin- 9(8H)-yl)-N- ethylacetamide

Example 37 2-(Imidazo[1,2-a]pyridin-3-yl)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one a) 2-Chloro-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-4,5-diamine

Following a similar procedure to that described in example 1 section d, but using the compound obtained in example 1 section a instead of the compound obtained in example 1 section c the desired compound was obtained (quantitative yield).

LC-MS (method 1): t_(R)=6.73 min; m/z=229 (MH⁺).

b) 2-Chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one

Following a similar procedure to that described in example 1 section e, but using the compound obtained in the previous section instead of the compound obtained in example 1 section d, the desired compound was obtained (83% yield).

LC-MS (method 1): t_(R)=7.16 min; m/z=254 (MH⁺).

c) 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one

Following a similar procedure to that described in example 5, but using the compound obtained in the previous section instead of the compound obtained in example 3b, the desired compound was obtained (58% yield).

LC-MS (method 1): t_(R)=7.51 min; m/z=288 (MH⁺).

d) Title Compound

To a suspension of the compound obtained the previous section (30 mg, 0.11 mmol) in EtOH (0.5 mL) and dioxane (1 mL), imidazo[1,2-a]pyridine (16 mg, 0.13 mmol), triphenylphosphine (5.8 mg, 0.02 mmol), potassium carbonate (3.1 mg, 0.22 mmol) and palladium (II) acetate (2.5 mg, 0.01 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 110° C. for 10 min and a 90° C. for 3 h. The reaction mixture was filtered through a plug of Celite® and the solvent was concentrated off. A sample was purified by preparative HPLC.

LC-MS (method 4): t_(R)=1.55 min; m/z=351 (MH⁺).

Example 38 Inhibition of JAK3 Activity

The inhibition of JAK3 kinase activity was determined in 384-well assay microplates using the Z′-Lyte® Kinase Assay kit-Tyr 6 Peptide kit, supplied by Invitrogan (Ref: PV4122), following the manufacturer's instructions.

In a final volume of 10 μL per well, 2.5 μL of the product to be tested dissolved in 4% DMSO (final concentration of the product to be tested, 0.1-10000 nM) was incubated with 0.3 μg/mL of the catalytic domain of human JAK3 (amino acid sequence 281-1124), 2 μM of the substrate peptide Z′-Lyte® Tyr 6 and 4 μM of ATP; all components were dissolved in 50 mM pH 7.5 Hepes buffer, 10 mM Magnesium chloride (II), 1 mM EGTA and 0.01% Brij® 35. The reaction was started by the addition of said 4 μM ATP; after incubation for 1 hour at 25° C., 5 μL of A Z′-Lyte® Tyr 6 development reagent was added and the mixture was incubated for 1 hour at 25° C. Phosphorylation was then quantified in each well using a Safire2® fluorescence microplate reader from Tecan.

The compounds 1 to 1b, 1d to 1j, 1n to 1p, 1s, 2, 2e, 3 to 3e, 3h to 3i, 4, 4b to 5i, 5s, 6 to 6b, 6d to 6f, 6x, 7 to 7d, 7f to 16a, and 16c to 17a, 17c to 19, 20 to 29, 31 to 37 showed more than 50% inhibition of JAK3 activity at 1 μM this assay.

Example 39 Inhibition of JAK2 Activity

The inhibition of JAK2 kinase activity was determined in 384-well assay microplates using the Z′-Lyte® Kinase Assay kit-Tyr 6 Peptide kit, supplied by Invitrogen (Ref: PV4122), following the manufacturer's instructions.

In a final volume of 10 μL per well, 2.5 μL of the product to be tested dissolved in 4% DMSO (final concentration of the product to be tested, 0.1-10000 nM) was incubated with 0.5 μg/well of the catalytic domain of human JAK2, 2 μM of the substrate peptide Z′-Lyte® Tyr 6 and 16 μM of ATP; all components were dissolved in 50 mM pH 7.5 Hepes buffer, 10 mM Magnesium chloride (II), 1 mM EGTA and 0.01% Brij® 35. The reaction was started by the addition of said 16 μM ATP; after incubation for 1 hour at 25° C., 5 μL of A Z′-Lyte® Tyr 6 development reagent was added and the mixture was incubated for 1 hour at 25° C. Phosphorylation was then quantified in each well using a Safire2® fluorescence microplate reader from Tecan.

The compounds 1 to 1b, 1e to 1g, 1n to 1p, 1s, 2, 2e, 3, 3b, 3d, 3e, 4, 4c, 5, 5a, 5b, 5e, 5f, 5h, 5i, 5s, 7 to 7c, 7f to 7n, 7p, 7r to 7u, 8 to 8c, 8d, 8f to 8h, 9a, 9b, 9c, 9f, 9g, 9i to k, 9m to 9s, 10a, 10b, 10e, 10h, 10i, 10k, 10l, 10m, 10n, 13b to 13k, 15 to 15b, 15f, 15h, 15i, 15k, 16, 16a, 16d to 16f, 17 to 17c, 18a, 18b, 18d to 18i, 19, 20, 21a to 21d, 21g to 21i, 21k, 22 to 23, 23d, 24, 24a, 24b, 24c, 25, 26, 26a, 26c, 26d, 26e, 26f, 26g, 27, 27a, 29, 31, 33, 34, 34b, and 35 to 36a showed more than 50% inhibition of JAK2 activity at 1 μM in this assay.

Example 40 Determination of Clearance in Human Liver Microsomes

A single concentration (1 μM in pH7.4 buffer) of a compound to be tested was incubated with human liver microsomes for 0, 10, 30 and 60 minutes at 37° C. (0.4 mg protein/mL). The degree of hepatic metabolism was measured by LC-MS/MS as the decrease in the peak area of the parent compound and expressed as the intrinsic clearance.

Several compounds of the invention were tested in this assay.

Example 41 Cytotoxicity in Hep G2 Cells Assay

Alamar blue (A) was used to evaluate the possible toxicity of a compound to be tested on Human hepatocyte carcinoma cells (HepG2). The cells (20000 cells/well) were cultured in 96-well plates in the presence of the compound at different concentrations (1 to 20 μM) containing 0.2% DMSO for 72 h at 37° C. After addition of AB, fluorescence was measured. EC₅₀ value, defined as the concentration of the compound that results in a decrease in AB fluorescence equivalent to 50% of the control, was calculated.

Several compounds of the invention were tested in this assay. 

The invention claimed is:
 1. A method of treating at least one disease selected from the group consisting of leukaemia, lymphomas, glioblastoma multiforme, colon carcinoma, and idiopathic myelofibrosis in a subject in need thereof, comprising administering to said subject an effective amount of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile or a pharmaceutically acceptable salt thereof.
 2. A method of treating at least one disease selected from the group consisting of rheumatoid arthritis and asthma in a subject in need thereof, comprising administering to said subject an effective amount of (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile or a pharmaceutically acceptable salt thereof.
 3. (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidin-1yl)-3-oxopropanenitrile or a pharmaceutically acceptable salt thereof.
 4. A pharmaceutical composition comprising (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 